Postmodern Superheroes
System: GURPS 4e, Mutants and Masterminds 3e (not 2nd), or Wild Talents.
Setup: Players are the setting's first superheroes in an otherwise normal-seeming contemporary Earth setting. There might have been some powered beings before them, but nothing that anyone's aware of.
Characters: Low-powered/street level to start, possibly growing more powerful with time. The players make their "base" normal characters, then at some point in-game they get their origin and the GM assigns them powers. They get minimal input into what these powers are, but do not define the actual mechanics, which they must discover -- slowly -- throughout the course of play.
Themes: The realistic affect of transhumanism on the psychology of the individuals involved, and should they fail to hide it, its sociological ramifications on the world. This is not a wish-fullfilment game about having kewl powerz, it's a game about what it's like to become more or less human. Of the highest importance is the sense of genuine human reaction.
Gameplay: Character driven with a plot. The players should be free to react however they feel is psychologically genuine, but have to face potentially harsh consequences for such behavior. Want to put on a cape and beat up criminals? Hope you enjoy anti-vigilantism laws and endless civil lawsuits from everyone involved.
For the GM this will be an exercise in extrapolation.
There should be a larger plot present that the players probably shouldn't ignore, but if they do, there should be consequences for that, too.
Finally, I'd prefer a game with 4-8 characters.
Tall order, I know. A long shot. But that's what I want to play.