Next up, George O'Malley and Mark Sloan. Lexie had a crush on George, who had to repeat his year as an intern. Mark Sloan noticed her infatuation to George and promised to ease up on him if she would admit her feelings. Lexie's "relationship" with George finally ended when he passed his intern exam. There were a lot of things Lexie would put up with, but George not even requesting her as one of his new interns wasn't one of them.

After the whole George debacle, the friendly flirtation between Mark and Lexie intensified. The hospital was abuzz with rumors of these two hooking up, but it just wasn't true...at least not at first. Lexie became very impressed with Mark after she witnessed him perform a difficult surgery. Later, she showed up at his room, one thing led to another, and they ended up sleeping with each other. Mark would've liked to pretend this was just a one-time thing, but was forced to confront his feelings about her. These two eventually become official after some very difficult situations, including Lexie injuring Mark's penis and Derek breaking Mark's hand.