To start, I would make a continuation of the game, (seems the natural thing to do, since they did this from D1 to D2) but have it a few generations later. After all the character classes helped fight for surival, some found things they liked about their allies in arms. So after some time, you get a mixing pot of characters and skills that meld things together. While others find a new path to follow.
This is a brief description of the characters and some of the skills:
Some Paladins loose their faith and find comfort in the dark arts of Necromacer skills, creating "Fallen Paladins" or also known as Faladins. These Faladins summon steeds much the same way as Necros summon golems. Magics tap into hidden powers that let a Faladin to think of a weapon and create this image into an actual tool of destruction.
Druids discover the power of other elements, but completely discard the companionship of beasts, to truely become one with nature. They become Elementalists, who summon their very surroundings of Earth, Wind, Water, and Poison into living forms that takes over them. Each such element comes with their own special traits and skills, but certain high lvl Elementalists with such faith in their skills have been known to combine 2 or more elements to aquire devistating skills like "Hail" a mixture of the wind and water elements. (basically blizard, that does added critical strike, open wounds, stun, and knockback with added damage as the skill progresses)
Necromancers seeing what death is like unbound, many find the lighter side of things and see life to be worth saving. Amazingly enough they are the ones who become the healers or Clerics. Studing the body for years they know what is needed to heal, or to hurt. They find new forms of surival with new skills, like astrail projection which can be used on one self or another to take a soul out of its body to prevent it from damage, or to cause great trama. The new party friendly Cleric can cast damaging curses to enemies while casting enhancements on allies. Also studing the basic structure of bones, they have become dependent on gear completely made from the dead giving them the guise of a animated skeleton.
Assassins, at their core are a guild of mercenaries for hire, but when they join in the fight to destroy the prime evils they put aside their selfish thoughts of fourtune, and are forever cursed. This curse creates a split personality where their very shadow takes on a life of its own. The assassin looses all knowledge of trap making and is left with its killer hand to hand abilities of martail arts, but the shadow, or Spector, becomes a trapper of dark. In a single movement they can travel great distances threw interconecting shadows, as well as call in aid from any and all other shadow like figure around. They are immune to all physical damage, but are very weak to every element.
The Barbarian natural born leader with hand to hand fighting and brute strength unmatched my most found weakness in the skills of magic. To proud to find fault they found a new form of fighting. Threw the art of magical tatoos, these fighters find many enhancements to the skills they already have within the body art, from increased abilities to mystical compaions.
As women of the forest, most have never seen the opposite sex. This fasination leads to offspring that are oddly enough all men. Passing on their knowledge of the bow and arrow the male amazons known as Rouges become silent but accurite killers, while their female counterparts retain the Javalin as the primary skill.
After seeing the awe inspiring power of the paladin, and their faith in a hire being, the Sorceress society allowed men into the order. After doing so they unified in a discovery that a sorceress or Witch was devoted too heavily on one element, and began the change to intergrate all 3 of their known elements together, but also learning a bit more about the basics of melee combat. Seeing this devotion, the Mage in the order seek to find their own element gods to worship. They are blessed with offering of the Earth, Water, and Poison. With this comes the ability to become nearly immune to their chosen element, as well as enchanted with powerful spells within that trait.
Ramblings and Ideas:
Only thing I constantly think of is that the prime evils were not destroyed but returned to their original realm of existence. What if someone/something accidentally found a way to open a doorway from 1 realm to the other.
Half the game will be fighting in this realm, while the other is inside the doorway to the other realm. Only real drawback is all the gear you have aquired will have negative effects on the other side. So lets say your armor give +5LL over 5 sec. In the other realm that would be -5 Life drain over 5 sec. and so on. This could also start the beginning of cursed Characters that wear nothing but items from the other realm. (Think of it no one can become "godly, leet, ect." in both worlds without amasing crazy amounts fo gear.)
You can fight your way threw a interactive inviornment that has some effects on you. Example would be if you fight at night, if the enemy does not see you their def is less. Wind could cause knockback, swamps could cause, slow by walking threw it, a posionous fog that lowers resistence and life.
I would love to see variations in areas, enough with the dungeons, caves, and buildings, I say bring on roped bridges between trees high abouve the ground, arenas where you can fight against the best builds imaginable,(picture walking into an area full of statues of Bone necros, Hammerdins, Multi elemental sorces, Rabies werewolf ect, but have one come to life to fight you as a quest you must defeat it) This could be used as a dueling area, swamps with poisonous fog, blizardous mountainsides, sealed tombs known as the primal tombs. I would love to see the hometowns of some of the characters like Necros, Sorceress, Druids ect.
It could be broken down to 10-20 quests in a area, another area for more quests but make everything harder to a slight degree. Basically instead of normal, nightmare, and hell, just have the player move to another area where the danger is increased. This would eliminate the boring repetaition of doing the same quests for all difficulties.
The Primal Tombs where you need to combat against a lesser prime evil, finally a decent and fitting ending of facing all the lower bosses at 1 time(Andy, Durrel, Pindle, ect.). After defeating this the tomb will open to anther area. This will be a single walkway full of mirrors on both sides where you will face off against a clone of yourself, and maybe even varients of what other builds you could have made. Each 1 defeated will shatter the glass, after defeating the doppleganger of yourself (this could be an area to gain a auto lvl or 2 like the ancients.)The last mirror shatters revealing the last room.....
All 3 prime evils fighting at the same time, each with their own minions under their command. (can you imagine the exp gained in this 1 room with 7 other allied palyers)
As a bonus anyone who can max out the character lvl of 99 has a choice to switch the character to a non human race, but this would put them into another play area of non human characters, and at lvl 1. You could have a Minitor as a barb, Banshee as a Sorc, Elf for the Amazon, Vampire as a Necromancer(what a stretch huh) ect. This would soulve the arguement of being a human or non human.
EDIT
[glow=black]SORRY GOT OFF TOPIC A BIT[/glow]
Since Cain is a old fart in D2 I would make it that his apprentice, trying to perminently stop the demons from coming into our world, but messes up 1 little thing and it has a reverse effect. The barrier from our world and theirs is torn right in the center of a thriving town. Demons begin to flood threw. The storyline would follow this apprentice and his allies, as they fight back against evil. Realizing they need to attack the monsters at its source they venture into the rift, and find out that it is a 1 way trip for the living. To make matters worse, they fight they realize their is no saving any of them from becoming tainted by the powers of evil within this world. So to save humanity, they decide to close the rift, by sacrificing themselves. No happy ending but at least closure.