For fantasy D&D, my top pick would probably be the Forgotten Realms, assuming:
1) the 3e Campaign Setting book is a reasonably-accurate but out-of-date description of the world;
2) earlier Realms products are in-character historical documents with unreliable narrators; and
3) later Realms products are wild tales told by bards, so I can pick or choose what's actually true.
I've also had fun with Dark Sun (incidentally, if you want an alternate Forgotten Realms, the Tablelands fit perfectly inside the Anauroch desert); Eberron (which I suspect I'd enjoy more with some system other than D&D, though I haven't had a chance to try it); and various combinations of Planescape, Spelljammer, and/or Ravenloft.
For science-fantasy, I've always been fascinated by 40K, though most of my knowledge of the setting comes from the old Rogue Trader rules, the Genestealer boardgame, and the relevant chapters in the original Realms of Chaos hardcovers. I've never really played with the setting much, but I appreciate its over-the-top aesthetic.