First of all, I love 4E. I think it's by far the best version of D&D ever. But here are the changes I'd most like to see:
1) A re-visioning of the resource management model that goes even further in combatting the 15-minute-workday syndrome. Something that removes any benefit from stopping for a long rest (beyond getting the minimal amount of necessary sleep per actual day), and at the same time gives the PCs the ability to carry on and engage lots of encounters without needing a full rest, through some means of restoring their powers and healing surges as they go, on a limited but renewable basis. Also, I'd like to see some degree of randomness injected into the whole resource-replenishment process, so that things aren't so metagamey (as far as knowing that doing X amount of encounters will automatically restore some resources). I'd like to see the PCs' skills matter to the resource management system, too, with Endurance checks, Heal checks, and an actual necessity (or detriment in lacking) for adequate food, water, and sleep.
2) A more robust and flexible multiclassing option. I don't think we should go back to 3E's unbridled craziness, but I think there should at least be SOME way for a character to have all of the core class features of two different classes, if they're willing to sacrifice something to do so.
3) A meaningful alignment system. I don't want alignment to go away, but I want it to be dynamic, reactive to in-game events and character decisions, and actually IMPORTANT (mechanically as well as socially) in the game. Something like the old Neverwinter Nights sort of system, where each character's alignment slides closer to good or evil, law or chaos, depending on what they do, say, and choose. And then some actual, concrete EFFECTS of those alignment polarities.
