Mechanical? Fluff? Both?
Mechanics-wise, the move away from 100% per-day power for casters. I think moving the majority of their abilities to per-encounter or at-will will do a lot for making them both easier to play and less apt to hoarding their abilities (or, alternately, less apt to blowing the living daylights out of everything in the first encounter then resting for another 8 hours).
Fluff-wise, I'm ecstatic about the Points of Light campaign framework and pretty happy with the planar changes, at least as a source of inspiration. I'm planning to run my first campaign in 4E as a homebrew, so fluff changes are mainly a source of ideas for me rather than mandates.