There are many aspects of playing through D2 that don't change much from one character to the next, so this post will go over some of those. For my purposes, I'm assuming a character playing without having future equipment ready in advance (i.e. "untwinked").
While working on this post, I realized I was throwing around a lot of terms and acronyms that might not make sense to newcomers to D2, so here's my attempt at defining them:
Breakpoint: A key value at which point a certain attribute (usually FBR, FCR, FHR, or IAS) has an effect. These vary by class (and sometimes by other details). For instance, a barbarian needs 20 total FCR to achieve 11 frames for their spellcasting animation and 37 FCR for 10 frames. There is no difference in spellcasting animation for a barbarian with 20 FCR or with 36 FCR. Here is a reference for FBR/FCR/FHR breakpoints.
Build: The totality of a character's class, stats, skills, equipment, strategy, and tactics.
Cap: A coded limit on how high/low a certain number can go.
Caster: A character who gets most/all of their damage output from skills and/or summons.
CBF: "Cannot be frozen", a possible equipment attribute.
Cube: Short for "Horadric Cube", a special item found in Act 2. Also used as a verb for making use of its transmutations (e.g. "3 chipped topazes can be cubed into a flawed topaz").
FBR: "Faster block rate", a possible equipment attribute.
FCR: "Faster cast rate", a possible equipment attribute.
FHR: "Faster hit recovery", a possible equipment attribute.
Frame: A single snapshot of visual display. D2 is animated at 25 frames/second (25 fps).
FRW: "Faster run/walk", a possible equipment attribute.
IAS: "Increased attack speed", a possible equipment attribute.
Magic find/MF: Shorten of "Better chance of finding magic items", a possible equipment attribute.
Max block: A character with sufficient DEX to reach the 75% cap for their chance to block attacks with a shield.
No block: A character that doesn't invest in DEX to increase their chance of blocking attacks with a shield.
Physical attacker: A character build whose damage output depends on their weapon heavily.
Respec: Short for respecification, this means clearing your current stat and skill point expenditures and reassigning them. One respec is given at each difficulty as a reward for completing the Den of Evil quest. Further respecs are possible but require killing act bosses multiple times for specific random items.
Runeword: A special set of item attributes made by inserting specific runes in a specific order in non-magical (i.e. name written in grey text) items with open sockets. Note that the item's total number of sockets must match the number of runes (e.g. putting Amn rune and Tir rune in a sword with 3 sockets will not make a Strength runeword). Take care that certain runewords can only be made while playing online in Ladder-mode or in single player with mods.
Skills: The potential special abilities of a character. Each class has 30 skills, split into 3 "trees" of 10 skills each, which can be seen in the skill tree tab ('T' hotkey by default).
Spells: Skills that do not involve/require hitting with a weapon's attack.
SSF: Short for "solo/self-found". See untwinked.
Stats: The four numbers on the left side of the character information tab ('A' hotkey by default): strength (STR), dexterity (DEX), vitality (VIT), and energy (ENG).
Untwinked: A character that finds all of the equipment it uses, without trading with or getting hand-me-downs from other characters played by people (i.e. shopping with the AI merchants is acceptable).
For the most part, there are two ideal sets of endgame stats to aim for:
Set 1: No Block
STR – Enough for equipment
DEX – Enough for equipment
VIT – Everything else
ENG – Nothing
Set 2: Max Block
STR – Enough for equipment
DEX – Enough for desired block rate
VIT – Everything else
ENG – Nothing
For characters that don't depend on weapon damage (i.e. characters for whom damage output comes from skills), a final STR of about 60-70 is usually sufficient. There are certainly items that can require more, but unless you actually find that gear, investing points in STR means having weaker defenses for no return.
For characters that do depend on weapon damage, the target range depends on what weapons you expect to use. You can look at sites like Arreat Summit or the Dii.net wiki for lists of equipment to see their stat requirements. Specific targets for this depends on the class/build, but generally speaking, axes give the best balance of damage-to-stat investment for melee weapons, swords require the least extra investment for someone aiming for max block, polearms have the best damage/range for two-handed weapons, and bows give better performance for less investment than crossbows.
To see your block rate, you can hover the mouse cursor over the defense rating on the character information tab. 75% is the highest that this can get, though it's certainly acceptable to aim for lower value (e.g. the last amazon that I cleared the game with aimed for 65% block rate because I didn't think that extra 10% was worth the loss in VIT). Whether it makes sense to go for max block depends on two factors:
(a) Your class and build, since those determine how much life you're giving up by investing in DEX instead of VIT.
(b) The listed block rate of your shield, which influences how much DEX it takes to reach max block.
Keep in mind that you need to add some DEX every level in order to maintain your desired block rate. For shields with a base block rate around 55%, this tends to be 2 or 3 DEX per level. Max block is generally not worthwhile with shields that have lower block rates (except for paladins who can boost block rate with their holy shield skill), and it's obviously worthless for characters using two-handed weapons.
VIT is the most important stat because it's almost always your main source of life. Additionally, red potions have a hidden chance to give a critical heal depending on your VIT score, scaling from about 5% to 50% for VIT scores under 200 and then approaching 90% asymptotically for higher scores.
Conversely, ENG tends to be the least important stat because all it does for most characters is reduce how often they use blue potions (both because they can use their skills more often before running out of mana and because it also increases the chance for blue potions to give a critical heal). In other words, it just grants short-term convenience at the cost of short- and long-term durability.
That all said, these are endgame targets. Thanks to gaining a respec at each difficulty for completing the Den of Evil quest, there's nothing wrong with assigning stat points differently in the earlier parts of the game and then changing them later on. If you're doing fine for life but drinking blue potions constantly, it can be reasonable to invest some 5-20 points in ENG with the plan to move them into VIT later on, once you have higher mana from leveling up and/or finding equipment with +ENG or +mana attributes. Similarly, even if you want a max block build, there's little point in boosting DEX early on (unless you need it for equipment) because early game shields have such low block rates that you can often survive more attacks by increasing VIT instead. Once you have a shield with decent block rate, then you can consider a respec.
Important Equipment Attributes
All characters benefit from the following (in no particular order):
+skills: Makes you a bit better at whatever your skills do. Just make sure it's applicable (e.g. if you're playing an amazon, an amulet with "+1 to assassin skill levels" does you no good unless it has other useful attributes). Note that every class aside from paladins has certain equipment only it can use that always has a chance to generate with +skills on top of any other attributes, as can wands (for necromancer skills), scepters (for paladin skills), and staffs (for sorceress skills), which often makes them great base items to use for runewords.
+resist: This is percentage damage reduction for fire/cold/lightning/poison elemental damage. Fire and lightning are the most valuable overall, since those tend to be the most damaging. Cold resist is also nice, but bear in mind that it can be increased temporarily by drinking thawing potions (+50 cold resist for 30 seconds per potion, timer is cumulative if drinking multiple potions) and the danger from cold attacks tends to be more from slowing your character than from raw damage. Poison resist is the least valuable since poison damage by itself can't kill your character unless the first tick of damage brings you to zero life, the damage over time can be offset by drinking red/purple potions, and poison resist can be increased temporarily by drinking antidote potions (similar to thawing potions). Resists normally cap at 75%, but this can be increased with certain equipment (thawing/antidote potions also increase the cold/poison resist caps, respectively, by 10 for their duration).
Poison length reduced: Poison damage is dealt by a combination of damage/frame and frame duration, so reducing the length drops the total damage and combines multiplicatively with poison resist. It's not of huge value for the same reasons that poison resist itself isn't, but it is worth treating as having some value when comparing equipment options, particularly since Nightmare and Hell difficulties include a hidden penalty to poison length reduction.
Damaged reduced: This reduces incoming physical damage. Note that the presentation is important! If it just has a number, that is a flat damage reduction per hit. This can be useful in Normal and even Nightmare, but it tends to be too low to matter in Hell unless purposefully stacked. If it has a percentage, that works the same as resists and becomes more useful in Nightmare and especially Hell. Also note that the similar-looking attribute "Magic damage reduced" is far less useful since that often comes in bigger chunks than physical damage (thus flat reduction per hit is less useful) and there is a limit to how often it applies against continuous damage (from standing in fire, most commonly).
CBF: This is a rare attribute (only comes on certain unique, set, and runeword items), but it's extremely valuable to avoid being slowed down when taking cold damage. Note that this does not affect the slowing from holy freeze auras (such as Duriel).
Half freeze duration: The weaker but far more common version of CBF. I wouldn't prioritize this highly, but it's worth giving some consideration because you aren't going to always have a thawing potion on hand to drink when you get frozen (especially with the long freeze durations of cold enchanted monsters in Hell). Keep in mind that multiple instances of this attribute do not stack and that it's worthless if you have CBF.
+FRW: Positioning and movement speed are incredibly important in D2. Not only does this help with avoiding ranged attacks, it also helps with moving through spaces before the path can be blocked off by enemies, avoiding being surrounded, manipulating enemy movements to improve efficiency of area attacks, and more. If you're new to D2, you'll probably want to focus more on more predictable forms of increasing survivability (like +resists or +life), but as you get better at the game, you'll be better able to use movement to reduce/eliminate risks. Best of all, unlike many modifiers, there aren't any breakpoints or caps for FRW, though it does suffer from diminishing returns for each source (from equipment or from skills).
+life/VIT: Since losing all of your life means death, the value of these should be obvious.
+STR/DEX: These can be equivalent to gaining the same amount of VIT if they reduce how much you're investing in the respective stats.
+FHR: Whenever your character gets takes at least 1/12th of their maximum life in damage in a single hit, they got through a hit recovery animation, during which they are essentially disabled. This attribute reduces how long that lasts. Bear in mind that there are certain breakpoints that dictate how effective this is (i.e. it works on a step function instead of a continuous curve), so you may not actually get benefit from adding more, depending on your class and possibly other factors.
+FCR: This is similar to FHR but for spell casting animations. If nothing else, this is very important for anyone trying to teleport or town portal away from a dangerous situation.
+FBR: This is similar to FHR but for shield blocking animations. This is obviously more important for max block builds, but even if you're going for a no block build with zero investment in DEX, if you're wearing a shield, there's always a chance that you'll block with it (although I'd give it very low priority in this case).
MF: This increases the odds for an item to be of a higher rarity (unique, set, rare, magic, normal, in descending order). This has no effect on the type of item dropped, so it has no impact on finding runes, gems, potions, etc. Every point of magic find suffers from diminishing returns in the item generation calculations, so it's usually not worth going for more than about 50-100 total MF if that means sacrificing survivability or killing speed unless your main priority is finding items.
Physical attackers tend to benefit from:
IAS: Needing less animation time to do your attacks both increases your damage output over time and reduces how much time you're spending locked in one place. Similar to FHR/FCR/FBR, this has breakpoints, but the exact values vary depending on weapon base speed, attack skill, and what sources the attribute is coming from, so you'll need to either test in play or use a calculator to see if you're really gaining from adding more. Also, be aware that werewolf/werebear druids and whirlwind barbarians gain little to no benefit from this attribute on equipment other than their weapons.
Attack rating: Unless you're using smite or guided arrow, you'll need to pass a hit check before you can deal any damage with a weapon. Hovering over your total attack rating on the character information tab will show a percentage chance to hit the last monster that you attacked; this number tends to be wrong since the calculation for that display is different from the actual to-hit formula, but it's usually in the right general ballpark. Most attacking skills have some modifier to attack rating, so it doesn't take much to get a respectable chance to hit, but ignoring it completely can have bad consequences. Additionally, comparing the levels of the attacker and defender also factors into the to-hit formula, so it's important not to rush ahead brazenly if you're having trouble hitting.
Enhanced damage: This is always good, though its value depends on where it's coming from. The way weapon damage calculation works in D2 is to take the damage from the weapon's base range, multiply that by the weapon's enhanced damage, add any flat damage additions, and then multiply by the sum of all other sources of enhanced damage (including from skills and stats). Thus, enhanced damage on the weapon itself is always the most valuable, and off-weapon enhanced damage (sometimes referred to as "oED") is far more valuable with low-damage skills like whirlwind than with high-damage skills like fury. Note that ethereal weapons effectively get +50% to both minimum and maximum damage BEFORE multiplying by on-weapon enhanced damage, which is what gives ethereal weapons with a self-repair attribute (or ethereal weapons used for runewords that grant indestructible) so much potential power. Also note that "damage to demons/undead" is a different attribute that works as oED, even if it is on a weapon.
+Minimum/Maximum damage: This gets added to the damage calculation before multiplying by off-weapon/skill/stat enhanced damage, so the actual amount of extra damage tends to be much more than the listed value. +minimum damage is slightly more valuable since increasing a weapon's minimum damage above its maximum will reset its maximum to "minimum+1", but that's not likely to matter beyond the early stages of the game.
+Damage: A very rare modifier (found only on the Grief runeword and two unique elite scepters), this works like +minimum/maximum damage except that it adds into damage calculations for the paladin's smite and the assassin's dragon talon/tail/flight skills. Highly valuable for those characters, and still great for others who can use it, but don't count on seeing this for an untwinked character.
Life/Mana stolen per hit: Commonly referred to as "life/mana leech', this allows physical attackers to function far more efficiently. Not only does it reduce reliance on potions, but even just something like 7-10% life leech can be crucial to improving survivability. Be aware that this only applies to physical damage and that certain enemies can't be leeched from!
Crushing blow: This gives a chance for any physical hit to take off 1/4th of a monster's remaining life after normal damage (cumulatively halved for champion/unique monsters and for ranged attacks), reduced by physical resist. This isn't much early on, but it makes a huge difference when facing monsters with 5-6-digit life totals in Hell, making melee characters with high crushing blow some of the fastest boss-killers in the game. Similar to CBF, this shows up only on unique, set, and runeword items.
Open wounds: This gives a chance for any physical hit to deal additional damage over time (the exact amount varies depending on the character's level). Not only is this extra damage not affected by any resists, but it also stops monster regeneration during its 8-second duration. Getting some extra free damage and stopping regeneration at the same time is good value, especially since it can still trigger on physical immune monsters as long as your attack can deal some elemental damage. Similar to CBF, this shows up only on unique, set, and runeword items.
Deadly strike: This gives a chance for any physical hit to deal double damage. For characters who have critical strike, the two effects are checked separately, but the effects are not cumulative (e.g. having 50% critical strike and 50% deadly strike is equivalent to 75% chance to double damage but does not have a chance to deal quadruple damage). A great way of increasing effective damage output. Similar to CBF, this shows up only on unique, set, and runeword items.
Casters tend to benefit from:
+Mana per kill: Since mana leech doesn't work with spells, this is the next best thing. The amount gained tends to be low, but since many spells can kill multiple enemies at once, the total recouped can actually exceed the mana spent in some cases.
+Mana regeneration: Nigh-worthless early on since absolute mana regeneration is a function of total mana, this can be helpful later on, particularly to allow yourself to get a clutch skill off just after being hit by a mana burn monster.
Notable Countess Runewords
Since basically all of your equipment is generated randomly, it can happen that your character just has a devil of a time finding equipment that covers certain needs. The most focused way of offsetting this is killing the Countess (a special enemy in Act 1) multiple times to get runes for making runewords. Below are some useful runewords for each difficulty, organized by item type and level required.
Note: Runewords marked "online ladder only" can be made in offline single player with the appropriate mods.
Normal (Countess drops up to Ral runes)
Stealth (Tal + Eth)
Made in body armor, requires level 17
Fantastic armor which could last you for the whole game, granting FRW, FCR, FHR, DEX, and poison resist. Almost all characters will want this early on.
Nadir (Nef + Tir)
Made in head armor, requires level 13
This is basically just for charges of cloak of shadows, which can be a lifesaver for characters who lack ways of handling enemy mobs, particularly in Act 3 and Act 4. Just be aware that it costs a fortune to recharge at shops, so you might want to keep some chipped gems and Ort runes in your stash to recharge it by cubing.
Leaf (Tir + Ral)
Made in staffs, requires level 19
Getting +3 to any single skill at this point in the game is incredible, let alone to all fire skills (note that this includes assassin fire-based traps, druid fire damage spells, and I think also to necromancer's corpse explosion and paladin's holy fire), and you also get a good chunk of cold resist on top. A sorceress can get even more out of this by making it in a staff that has bonuses to whichever fire spell(s) they use (fireball or firewall being the most likely for level 19).
Malice (Ith + El + Eth)
Made in any melee weapon, requires level 15
A reasonable early weapon for melee characters, this grants decent damage, attack rating, and chance for open wounds but lacks IAS.
Steel (El + Tir)
Made in axes, swords, and maces, requires level 13
Another reasonable early weapon for melee characters, favoring those who care more about IAS since the damage and chance for open wounds are both less than Malice. Note that "maces" is only the mace, morning star, and flail (and their exception/elite versions).
Nightmare (Countess drops up to Io runes)
Peace (Shael + Thul + Amn)
Made in body armor, requires level 29
This isn't as universally useful as Stealth, but it's the best offensive runeword body armor for physical attackers at this stage due to the +2 critical strike, and the chances of casting both slow missiles and valkyrie are helpful (though the valkyrie will disappear after about 5-10 seconds unless you have at least 1 point in that skill). Even better for amazons thanks to +2 amazon skills, but it's surprisingly good on many non-caster characters.
Lore (Ort + Sol)
Made in head armor, requires level 27
+1 skills (druids and barbarians can make it in their class-specific helms for even more skill bonuses) and a decent chunk of lightning resist. It's a nice package, and there usually isn't a lot of competition for head armors until at least the later stages of Nightmare.
Black (Thul + Io + Nef)
Made in clubs, maces, and hammers, requires level 35
Generally the weapon of choice for melee physical attackers in Nightmare, since 40% chance of crushing blow is huge, and it even has good attack rating and a bit of IAS, enhanced damage, and VIT bonus to go along with it. Don't overlook the charges of corpse explosion, either, though they can be expensive to refill. The knockback can be an annoyance, though, particularly for characters who do multiple hits per skill use.
White (Dol + Io)
Made in wands, requires level 35
Only really useful to necromancers using poison and bone skills (other characters can get the FCR from any random wand, at worst), but it's fantastic for them. I like it more than Spirit. Always try to make it in a wand with innate bonuses to your skills of choice for even more awesomeness.
Honor (Amn + El + Ith + Tir + Sol)
Made in any melee weapons, requires level 27
Often overlooked in favor of Black/Strength (for crushing blow) and Insight (for generally being better and more accessible, albeit online ladder only), this is a still a solid runeword that can be made in a number of axes from Normal Act 4/5/cow level or the early stages of Nightmare (swords and polearms can't get 5 open sockets until later parts of Nightmare). The lack of IAS is a shame, but +1 all skills, decent enhanced damage, good attack rating, life leech, STR bonus, and deadly strike are all nice.
Insight (Ral + Tir + Tal + Sol)
Made in polearms and staffs, requires level 27, online ladder only
Most often used with an Act 2 mercenary to more or less negate mana concerns with its aura, the great FCR, enhanced damage, attack rating, stat increases, and critical strike (effectively 16-46% chance to double damage) makes this a solid weapon for anyone who isn't concerned with attack speed. I wouldn't use this over Spirit for a caster, but I could see arguments for it with builds like whirlwind barbarian or blade fury assassin.
Edge (Tir + Tal + Amn)
Made in bows and crossbows, requires level 25, online ladder only
Great IAS, a nice bonus to all stats, and significant enhanced damage against demons and undead (just remember that this combines additively with other sources of enhanced damage). I think the "reduce all vendor prices" attribute is unique to this runeword, too, giving it some use even for characters who don't care about the weapon itself.
Spirit (Tal + Thul + Ort + Amn)
Made in swords and shields, requires level 25, online ladder only
An amazing runeword for casters (though necromancers have White and amazons don't benefit much), this is an easy source of +2 all skills on top of huge amounts of FCR, FHR, VIT, and mana. Note that a crystal sword, broad sword, or long sword found in the Normal Act 4/5/cow level always gets 4 open sockets from Larzuk's quest.
Strength (Amn + Tir)
Made in any melee weapons, requires level 25
The earliest runeword that grants crushing blow, which alone makes it worthwhile if only for killing act bosses. The life stolen on hit isn't worth much since this grants so little enhanced damage, but the huge bonuses to STR and VIT are always welcome. Black tends to be better, but this is much easier to make and can work in many more types of weapons.
Holy Thunder (Eth + Ral + Ort + Tal)
Made in scepters, requires level 21
While this is probably the weakest of the notable Nightmare runeword weapons and the number of runes required means it must be made in a war scepter (or divine scepter), it does add the most elemental damage as well as a hefty amount of lightning resist. A niche weapon, but potentially useful.
Zephyr (Ort + Eth)
Made in bows and crossbows, requires level 21
Another easy runeword for ranged weapons. This has less IAS than Edge in return for granting FRW and more attack rating. Depending on how it's being used, it may also deal more damage, though I'd expect Edge to win in that category for most cases.
Ancient's Pledge (Ral + Ort + Tal)
Made in shields, requires level 21
If you want a pile of resists without much concern for blocking, this is hard to top (particularly since you can get the runes as a reward for a fairly simple quest in Act 5, but they come up in enough useful early runewords that you might have other priorities for those).
Rhyme (Sheal + Eth)
Made in shields, requires level 29
Almost a must-have for many untwinked characters since it's by far the most reliable source of CBF. Add pretty nice resists, MF, and a good boost to block rate (for those interested in that), and it's hard to top. Necromancers can also enjoy making this is heads for some incidental skill bonuses, too.
Spirit (Tal + Thul + Ort + Amn)
Made in swords and shields, requires level 25
For most characters, this isn't as useful as Spirit in a sword because shields can't get 4 open sockets until mid-to-late Hell. For paladins, however, their class-specific shields can all get 4 open sockets (as long as they dropped in Normal Act 4/5/cow level or later). So, for them, take everything that's great about a Spirit sword, and give them a chance to double it. It's even suitable as a main shield, since holy shield can make up for the lack of increased chance to block (particularly with the +2 skills improving it).
Hell (Countess drops up to Ist rune; these generally aren't necessary to beat the game but can be nice upgrades to Nightmare equipment)
Delirium (Lem + Ist + Io)
Made in head armor, required level 51
Being one of the very few ways to get +2 skills from head armor and also having multiple chances to cast debuffs on hit is great. This will likely take dedicated effort to make due to needing an Ist rune, though, and there's always the chance of being turned into a bone fetish for an annoying (and possibly dangerous) amount of time when struck, too. Personally, this is my least favorite +2 skills head armor, and I generally wouldn't make it unless I happened to get an Ist rune while working towards another runeword, but it's certainly good.
Duress (Shael + Um + Thul)
Made in body armor, requires level 47
Getting crushing blow from a body armor alone is worth the Um rune for most physical attackers (only the unique armor Rattlecage also has crushing blow, and its other modifiers are generally far worse). Add on a huge amount of FHR, chance for open wounds, decent cold damage added, some resists, and even a splash of enhanced damage, and you've got a fantastic package. One of the best offensive armors in the game, unless you're playing a caster.
Gloom (Fal + Um + Pul)
Made in body armor, requires level 47
Of the three Um runeword body armors, Gloom provides the highest resists but the least FHR. I find it the least notable of the three; resists are generally far more important than defense, but if I really want a resist-heavy body armor, I'd tend to go with Smoke instead since Lum runes are far more common than Um runes. Still, this is certainly solid, the chance to cast dim vision is great for getting some reprieve from crowds, and 10% FHR is nice if it can push your character to the next breakpoint.
Stone (Shael + Um + Pul + Lum)
Made in body armor, requires level 47
Incredible FHR, incredible boosts to STR and VIT (and a good boost to ENG), and sky-high enhanced defense is great for characters built to take advantage of that. Clay golem is also a great summon due to slowing enemies, though it might feel fragile in Hell without a necromancer's summon resist skill. The resists could've been better, but this is still fantastic for many characters.
Treachery (Shael + Thul + Lem)
Made in body armor, requires level 43
This gives a ton of IAS (especially for an armor!) and some FHR. Use it for a bit in combat, though, and you'll often have 68% resists from the chance to cast fade when hit, while the chance to cast venom when hitting is almost like adding about 300 poison damage on hit. This makes it quite nice, though the unreliability can be off-putting. Amusingly, it's probably least suited for use on an assassin, since the armor's fade will override your own fade or burst of speed.
Lionheart (Hel + Lum + Fal)
Made in body armor, requires level 41
Huge amounts of bonus stats, nice resists (especially for the runes used), and even a splash of enhanced damage on top. This is a very solid armor for casters, and while physical attackers would surely prefer the crushing blow from Duress, this is still good for them while tending to be much easier to get. I'd say this is competitive with Smoke and Stealth for being the best bang for its rarity among body armor runewords.
Smoke (Nef + Lum)
Made in body armor, requires level 37
Amazing resists, and you even get some FHR as well. While I tend to prefer either Lionheart or Stealth, this can do wonders for freeing up your other equipment options while still keeping good resists in Hell.
Oath (Shael + Pul + Mal + Lum)
Made in axes, maces, and swords, requires level 49, online ladder only
Best made in an ethereal weapon to take advantage of the indestructible attribute, this can be one of the very best melee weapons (and even a low result for the enhanced damage is going to be very good). Ridiculous IAS, good-to-incredible enhanced damage, a high chance to cast bone spirit that gives it about another 120 rarely-resisted magic damage per hit, and even a bit of hidden extra effective damage for hit-and-run play thanks to the "prevent monster heal" attribute. The charges give some decent situational summons, though keep in mind that it can't be recharged if made in an ethereal item. Mal runes are rare, but this is a great use of one for a melee character.
Crescent Moon (Shael + Um + Tir)
Made in axes, polearms, and swords, requires level 47
A very interesting weapon, as the chance to cast static field is almost like getting an alternative form of crushing blow, and the penalty to enemy lightning resists helps both that damage and any other lightning elemental damage (whether added to weapon attacks or from spells; sadly, this doesn't work with an assassin's traps due to them acting as minions instead of part of her attacks). This tends to be most popular as an Act 2 mercenary weapon since they can't use Oath, but it can work as a main weapon, too.
Lawbringer (Amn + Lem + Ko)
Made in hammers, scepters, and swords, requires level 43, online ladder only
The combination of adding hefty elemental damage to every hit, having a chance to cast decrepify on hit, and sanctuary aura ignoring physical resist for undead means this is a surprisingly capable choice as a back-up weapon to deal with physical immune monsters. The lack of both IAS and enhanced damage does hold it back from being a good primary weapon for most characters, but those few physical attackers who don't rely on their weapon's damage (e.g. elemental zeal paladin or dragon talon assassin) can find it attractive, as might an Act 5 mercenary.
Passion (Dol + Ort + Eld + Lem)
Made in any weapons, requires level 43
My preferred of the Lem runeword weapons, this gives decent-to-nice amounts of IAS, attack rating, and enhanced damage, but perhaps most notable is that it lets any character use the skills zeal and berserk. The former can turn anyone into a formidable physical attacker with just a few +skills, and the latter allows anyone to deal damage to physical immune monsters. I find this especially interesting to use on amazons, assassins, or necromancers, when I want something different from their usual playstyles (though I'd reserve that for characters who I'm planning to twink).
Voice of Reason (Lem + Ko + El + Eld)
Made in maces and swords, requires level 43, online ladder only
Similar to Crescent Moon, except this trades off enhanced damage for adding significant cold damage on hit. The spells aren't as good as static field in most cases, lacking any IAS hurts, and penalizing cold resist isn't as valuable for a sorceress since their cold mastery skill does that already, though gaining CBF could open other equipment options. Very niche, but this is potentially useful for a paladin running holy freeze or as a backup to Crescent Moon for lightning immune enemies.
Obedience (Hel + Ko + Thul + Eth + Fal)
Made in polearms, requires level 41, online ladder only
Huge enhanced damage and crushing blow, plus great amounts of FHR, STR/DEX, and all resists make this a very attractive option. The chance to cast enchant won't add much damage on its own, but it does add 200% attack rating for 10 minutes per casting, so it's almost a permanent buff after it triggers once. I find the penalty to enemy fire resists is even harder to take advantage of than for Crescent Moon or Voice of Reason, but this has enough other things going for it that it's still pretty great for anyone who doesn't need IAS or a shield (like an Act 2 mercenary or a blade fury assassin).
Harmony (Tir + Ith + Sol + Ko)
Made in bows and crossbows, requires level 39, online ladder only
Good-to-great enhanced damage, a major boost to FRW thanks to the vigor aura, a good amount of added elemental damage (averaging 323 extra damage per hit before resists), and it lets everyone use arguably the best summon in the game (combine it with Peace armor to make that level 15 valkyrie stick around!). And if you want more summoning, it even has charges of revive! It's almost a shame that ranged characters aren't more common, because this is honestly incredibly good.
Melody (Shael + Ko + Nef)
Made in bows and crossbows, requires level 39
One of the best weapons for an amazon using elemental arrow skills, since +skills and IAS are their main concerns. Low enhanced damage makes this lackluster for other characters (including amazons using the middle column of that skill tree), but for elemental bow amazons, I'd prefer this over Harmony.
Memory (Lum + Io + Sol + Eth)
Made in staffs, requires level 37
If you don't mind giving up using a shield, +skills and big FCR makes this a good weapon for a sorceress. Sadly, it'll tend to be overshadowed by a Spirit sword, but for those playing without online ladder only runewords, it's worth consideration (particularly since sorceresses are the class least impacted by potentially giving up CBF from a Rhyme shield). Don't forget to try using a base staff with helpful +skills!
Sanctuary (Ko + Ko + Mal)
Made in shields, requires level 49
Incredible resists, and you also get some FHR, FBR, and increased chance of blocking. It's an upgrade from Ancient's Pledge for sure, but whether it's an upgrade from Rhyme depends on how much you value gaining resists against losing CBF.
Splendor (Eth + Lum)
Made in shields, requires level 37
If you don't need resists or CBF from a shield, this is a nice way to get +skills and some FCR from a shield without needing to get the STR for Spirit. It's a niche use, but if you can swing it, +skills is always nice.
Exceptions to Every Rule
D2 is a complex game, so there are few statements of universal truth about how to play. I'll get into more of those details with the upcoming class guides, but I hope this post can serve as a good foundation to build on top of. Until then, go kill some demons, and let your experiences foster growth.