I voted Planescape, since IMHO this is one of the most original and interesting settings ever produced by a gaming company period. It's got a multitude of adventure sites, a built in reason for a DM to create numerous prime material planes(or use those already published). accomodates a number of playstyles and actually goes beyond killing things and taking their stuff(though this is easily possible as well.)
Where else can you con a demon into giving you a tear or two and use them to open a portal, in a grime flecked alley of Sigil, to the world of a dying god. Have tea with her and wax philisophical about the nature of godhood and how she has grown tired of it. Then hire yourself out as her protector, (unless of course your an Athar, then you find a way to merk her and return to Sigil with her head as more proof gods aren't really gods), to battle the cult of insane githzerai monks who believe she's their new god, after which you've got to figure out a way to permanently put her to rest( maybe hunt down her remaining worshippers across the planes??).
I like some of the others (especially Dark Sun) but the gaming industry has expanded, and many of these settings may have been original when they were published, but now not so much. I still haven't found anything that stands up to Planescape in originality or adventure possibilities. This would probably be the setting that would have me purchasing D&D 4e.
