I voted for a few settings:
Mystara. It's an extremely well-fleshed-out world, with its own whimsical flavor and a ton of backstory. The high magic aspects of the setting could be a good fit for the 4e classes. Heck, some of the best modules in the history of the game were set here. If some focus was placed on the concept of adventurers being able to ascend to Immortality, there could be even some new mechanical material on what happens beyond the Epic tier of play. You could even play up some of the weird technology angle, what with the flying warships and forgotten Blackmoor weaponry laying around.
Birthright. I never played this setting when it was being supported, but I feel like a Birthright book could add a lot of aspects that were once core to the D&D feel back into the game. Getting a keep, carving out territory, gaining followers, managing a kingdom... even if the Birthright setting wasn't used, I would absolutely love to see a book that explores those topics.
Planescape. It remains a popular setting for good reason, though I will admit that a lot of its appeal for me came from legitimizing some of the more nonsensical aspects of AD&D. It's based so heavily on the old alignments and cosmology that it might be difficult to work out. At the very least, I would incorporate Sigil as a planar crossroads where the prime movers and shakers from across the D&D universe rub shoulders.
New settings. Others have complained that any kind of setting one can imagine has been done at some point or another, but I strongly disagree. For one, D&D has never had a well-supported sword and sorcery-type setting (as opposed to high fantasy). You know, bold adventurers surviving by blood, sweat, wits and steel. Less dragons and orcs, more bloodthirsty apes and big freakin' snakes. Less castles and dungeons, more crumbling temples and reeking, labyrinthine cities. Maybe something like Wilderlands of High Fantasy/City-State of the Invincible Overlord, but with less of the Tolkien high magic stuff grafted on.