In a new interview, Sara Ramirez has eluded to Callie dealing with George & Izzie's affair in a "shocking and empowering" way...which equals sex. But...sex with who? Alex, as has been rumored? Or, could it be Mark - again? We'll just have to wait and see.
On another note, in the same interview, Sara says this about the new season, which sounds incredibly promising:

"You know a lot of people last year had complaints about the direction of the show. It was dark. It was much darker than the previous two seasons and as a fan of the show myself I felt compelled at times to speak up and say, 'No no no! Put Derek and Meredith in the bed until they fix this!' or 'Stop with the cheating!', but if everything was perfect then that would be a happy ending and the story would be complete. So, I'm in it as a fan and an actor and I can honestly tell you that this new season is funnier, lighter, and several of the characters wake up. There's an awakening and it leads to new couples, new friends, and new paths. And those paths are very interesting."