Be all and end all
For me, I don't think there could be a "be all and end all" game - I like switching games and systems, although I tend to favor a few when it comes to GMing.
I like the fun factor of d20, the transparency of BRP (Chaosium's system), the basic pool system from Aberrant, character generation from GURPS...etc.
As far as a setting that would make me look no further, I've gamed the longest (and run the most games) in the Forgotten Realms and CoC's Lovecraftian universe - but I can't think of any setting that I would ever play exclusively.
Interesting question, though.