I know I posted this earlier, but seriously: don't do a fantasy game. At least not a traditional one. Fantasy's boring because there's so much of it. Everyone's all jazzed for Planescape 2, but I think that a similarly intelligent and contemplative game could scratch that itch without falling back on an old setting. Beyond that, the kind of SSMA-friendly approach to quests that you had in New Vegas is pretty much a must.
The most important thing IMO is a good setting. Traditional fantasy settings are boring and played out. It'd be cool to see a game with a real world setting, or a modern gothic fantasy thing like WoD, or some kind of inexplicable far future weirdness.