Serena's Upper East Side world is turned upside down when her former partner in all things bad, Georgina Sparks, returns to Manhattan to stir up trouble and Serena's past. When Dan notices that Serena seems preoccupied he jumps to the conclusion that it must have something to do with Serena's new roomie and soon-to-be step-brother, Chuck. Nate finds romance with the last person he was expecting to connect with, Vanessa. Jenny meets a new guy, Asher Hornsby, who just might be her ticket to permanent popularity. Finally, Blair hatches a secret plan to sabotage her biggest rival, Nelly Yuki.
Title comes from the 1985 film Desperately Seeking Susan.