EW has an exclusive with Eric Kripke who handed the show over to the awesome Sera Gamble for S6, go read the whole thing!
Okay, what is the new story line?
KRIPKE: One of the first things Sera and Bob talked to me about was that the angel thing is rightfully exhausted, so where do you go from there? Not to say that angels and demons won’t be a part of the story line, because they will. Castiel will be there. Crowley will be there. The beloved characters will be threading into the story. But the great undiscovered country of Supernatural is kind of right in front of our face: creatures and monsters. We have had so many creature episodes but we haven’t actually explained where they came from—[similar] to the way we have explored angels and demons. How do they feel about the situations they are in? Are they from here? Where did the first ones come from? How did werewolves and vampires and shape-shifters all begin anyway? I thought that was a really smart notion on [Sera and Bob's] part, just exploring the history of that, because that was something that we never investigated on the show.
How does Grandpa [Mitch Pileggi] fit into this?
KRIPKE: He’s representative of the other side of this exploration, which is that Sam and Dean have a family of hunters that they never knew they had. Their grandfather is the head of that family. Remember, it’s not the Winchesters who are famous hunters, it’s the Campbells. And we are saying that the Campbells are part of a timeline of hunters that have been there since the country’s origins. As Sera put it, they were hacking heads off vampires on the Mayflower. For Sam and Dean to really tap into a family history, which they never knew they had and again never really investigated before, is pretty interesting to us.
Want more scoop on season 6? You should definitely check out the show’s Comic-Con panel on Sunday, July 25, at 11:15 a.m, starring Jensen Ackles, Jared Padalecki, Misha Collins, and Jim Beaver, as well as EPs Sera Gamble, Ben Edlund, and Eric Kripke.