This is a lot harder that i thought as all of the characters, without exception, have such great back stories. (Were the series to continue, i think that they all would've had some very interesting story arcs.)
I'd have to go with Mal and River. I just think that from what we've seen, these two are the ones that the story is about. (Don't get me wrong, i love all of the other characters, but i can only pick two.