Birthright for me... I'd love to see realm rules for 4e... not to mention that Birthright had an awesome hook with the bloodlines and some of the best adversaries of any setting I can remember.
For myself, I'd say Ravenloft. But this time, take the 3E changes further and make it a fully contained and self-sufficient setting, instead of playing musical chairs with it's relationship with other settings (Soth, Jandar, I'm looking at you).
Of all the alternative settings of 2e, Spelljammer caught my interest more. The trouble is that high level adventuring that involves depending on a big chunk of fragile wood tends to throw things out of wack. Spelljammer is probably best left in the 5-12 level range. But if the rules can be expanded upon so that entire ships don't destruct from a single well-placed high level spell (or kill the entire crew), and the combat rules can integrate well with foot combat (more action, less moving and turning), I'd take a serious try at it again.
I'd actively like to see Spelljammer and Dark Sun updated. However, I'd like the updates to come in the form of:
1. A single hardcover (OK, I would like a softcover because that's what I prefer, but that's not gonna happen ) providing the basics of the setting, some key monsters, any new classes or races, and any other signature crunch (like the ship rules for Spelljammer).
2. Support in Dungeon and Dragon via the Digital Initiative.
3. Monsters updated in the generic monster manuals.
Spelljammer could work, IMHO, if it was done in a vein similar to the Shadow of the Spider Moon article in Polyhedron (had it's own assumed setting, instead of just plugging into everything else).
As others have stated, the fact that Birthright, while it didn't have to revolve around kingdom/realm maintanence and adventures, was great because it did. It opened my eyes to a whole new world of possibilities.
I think that the design team for 4e could really make this one extremely awesome.
Plus, and here I go again, the villians and plot hook for the PCs just rocked on toast... So to speak.