I think 4e deserves it own setting. Upgrading existing setting is all well and fun, but I'm itching for something new, something I can open the cover and read page after page of wonder.
I also wouldn't mind a shift in setting period. I realize Dark Sun does this going back in time, and Eberron does a good bit of this going forward, but going forward even more into the modern realm where certain technological (or technomagical) discoveries have been made, would be interesting.
There is also a lot that can be borrowed from sci-fi, gate travel between worlds, parallel universes, techno gods, etc.
I'm not really looking for originality, that's a tough order, but I'd love to see something new that's at least a little unorthodox.