But in truth, I think the toughest thing is to have a good SECOND season of a show. Especially since so many shows these days are built on a premise that is really only sustainable for one season.
The only show I can think of with a real one-season premise is
Prison Break. (I don't watch
DH.) Some like
Chuck and
Dexter have self-limiting premises that require a lot of creativity to squeeze, say, four seasons out of. That's a more common problem - probably because few shows survive that long so nobody bothers to create premises with legs.
Heroes is another example. I mean, where do you go from a season 1 ending like that? The seriously bad 'bad guy' is dead...and the main 'good guy' has accumulated all of the powers of the other heroes and so can, theoretically, kick anyone's ass.
Heroes is an example of an open-ended premise, like
Star Trek, because it's an unresolvable situation rather than a goal. If it had been handled properly, it had the potential to become a franchise with spinoff series (probably too late now).
You're just not thinking about all the possibilities that could be pulled out of that premise (that's ok, the writers aren't either

). The premise is: the world has people in it now with powers that make them a LOT more powerful than other people. That upsets the natural power structure of society and creates mistrust and fear which leads to all sorts of bad things. But the people with powers aren't going away and neither are their powers (I guess they could, but that would be a lame-ass resolution to the story, by simply negating the premise). So how does everyone cope?
That premise could go on forever, with a 100% changeover in cast if needed, either after the first season or just over time. They could kill Sylar and keep the show going - the premise doesn't demand Sylar's presence. What demands his presence is that the writers apparently can't think of anyone to replace him with as a central organizing factor, but they really should be able to do stuff like that and it's not the premise's fault that they can't. They could kill Peter, they could kill anyone. Or nerf Peter's powers, or Sylar's, or decide to turn them both in werewolves or give them the power to eat the planet (I better stop before I give them any brilliant ideas in case anyone's reading).