I have seen some versions of this in games, but I would like to see more: replace loot with a talent tree. Have something like LOTRO’s legendary item system, or otherwise just make the loot another skill/talent tree. Instead of finding a stream of disposable loot, with the occasional upgrade, just build the loot into the character. This especially goes for games with ridiculous amounts of trash loot, like Diablo or Borderlands.
We probably still need some sort of grind or loot accumulation, but build that in too. Instead of picking up vendor trash, have monsters drop crafting components. You need 200 green floozles and 10,000xp to give your staff Healing Floozle, whatever. It must be an easier setup than hundreds of different loot objects.
I am probably odd, and Diablo-style loot seems popular. People like that slot machine. I find it dull, and the occasional good hit on a slot machine makes the rest even more dull, because I know all the loot below color X is vendor trash. You know what rarely excites me in games? Vendor trash, nor its friend inventory maintenance.