Lately, I've been playing Diablo 2 again online with a friend, and I have been remembering how much I like the game. It's not a terribly complicated game; you make a character, and then just wander around and click on things to kill them in various ways. But I have always loved the setting and the ambiance of the game. I have thought at numerous times about using D&D to run a game in the world of Diablo 2, and I think it could be pretty easily done, especially with 4th edition.
For one, all the characters available in Diablo 2 are human; while there has been some evidence of intelligent non-human beings in the world of Sanctuary (where Diablo games take place), they are always portrayed as evil. So humans all 'round, though you could probably reskin some of the D&D races to be different human groups.
Second come the classes that characters play. In the original Diablo, the classes available (including the Hellfire expansion) were Warrior, Rogue, Sorcerer, Monk, Bard, and Barbarian. Warrior could pretty easily be a fighter, and a sorcerer from Diablo could easily be either a Wizard or Sorcerer in D&D. The Rogue could be kind of a D&D Rogue, but was really more like a ranger, and they were female, members of a women-only group called the Sisters of the Sightless Eye. The monk (who apparently will also appear in Diablo 3) seems like it could be used with the relatively new Monk class, and the bard in Diablo could be subbed in by the D&D bard. The barbarian gets covered in Diablo 2.
In Diablo 2, there were more classes available: the Amazon, the Assassin, the Barbarian, the Druid, the Necromancer, the Paladin, and the Sorceress. The Amazon is much like the Rogue in Diablo 1, and would most likely fit in as a ranger in D&D. The Assassin, luckily, could be covered by the new Assassin class released to D&D Insider subscribers - not terribly tough, but deadly in a fight. The Barbarian fits very well with the new D&D Barbarian, a damage-focussed combat machine willing to take damage to give more out. The Druid, with its shapeshifting and summoning skills, fits in with the D&D Druid, while the Paladin fits in as a D&D Paladin, though he doesn't receive auras, sadly. The Sorceress, like the Sorcerer in Diablo 1, could be covered by a Wizard or Sorcerer in D&D. The Necromancer has yet to find a place in D&D, but hopes are high that it will become a new class in the future.
Diablo 3, while unreleased, has shown several classes from the game. Two are old favorites, the Monk and Barbarian, while two are new, the Wizard and Witch Doctor. Wizard is an obvious use in D&D, and Witch Doctor, while a difficult fit, might be best served by the Shaman class, though until the game comes out it will be difficult to say.
The setting might be one of the easiest ports to D&D. With access to the Diablo wiki, and possibly either some of the novels or the manuals from the games, you've got most of the outline for a decent setting. The demon-beset kingdom of Khanduras, the desert port of Lut Gholein, the jungles to the east where the corrupt Zakarum religion holds sway, these are all great area for players to adventure in. With the cool thematic information for the various places, but few specifics, it leaves most of the world for a DM to create. The variety of monsters in the world of Sanctuary make monster use easy, though many of the typical D&D monsters will have to be renamed or fit into Sanctuary thematically.
A D&d game set in Sanctuary shouldn't be just about killing monsters, but about the perils of evil, and how it is very easy to lose your way. Many of the greatest heroes of Sanctuary end up corrupted by the Burning Hells; the great mage Tal Rasha took the soulstone of Baal into his body, and lost the fight with the demon lord's spirit. The Dark Wanderer, the victor of Diabo 1, defeats Diablo only to later become his reincarnation. The path is long and dark, and there are many dangers on it, but if you remain true, you can triumph.
At least, that's how I see it.