The Upper East Side is thrown for a loop when Gossip Girl reports that Serena van der Woodsen (Blake Lively), Manhattan's most notorious party girl, has arrived back in town after a mysterious absence where no one knows where she was or why she left. Not even Serena's closest friend, Blair Waldorf (Leighton Meester), knew her whereabouts and is shocked to learn Serena has returned. However, their once close friendship is complicated upon Serena's return, strained now that Serena is the center of attention and Blair has been cast from the limelight, and the revelation that Serena had a fling with Blair's boyfriend Nate Archibald (Chace Crawford).

Also ruling the Upper East Side is Chuck Bass (Ed Westwick), son of the wealthy and powerful Bart Bass and a friend of Nate's since childhood. Chuck leads a reckless life, which often leads Nate down a similar path of darkness and destruction.