There’s a couple of ways this one can be taken: the smartest game (either run or the smartest players…) or the smartest setting/genre, or the smartest rules set…

I’ll go with the middle one first. The smartest game I’ve ever played was is probably the one we’re trying out now — DIE the RPG. The meta-quality of playing characters who are themselves dragged into a game and playing their characters isn’t a new idea, but the system and the setting are designed to play with the foibles and issues of the characters as the world of DIE seeks to “feed” on their hopes and desires, fears and pain. It’s also the first game to explicitly have the GM be a character/player in the game that I can think of — the world is crafted by that player’s issues. It’s an interesting aspect that can really be fun for the GM.

The smartest game as in the storyline, players’ actions, etc. has got to be the Battlestar Galactica campaign I ran for years. Running a game in an established property is tricky, especially one where the story is has already been told and has it’s own heroes — think Babylon 5, for instance, that was tricky to create a story that allowed the players to have real impact when Sheridan and the others are running around deciding the fate of the galaxy, of Star Wars — where you’re not going to get to destroy the Death Star or take out the emperor; or even Star Trek, to a point.