Season four's main mystery revolves around Juliet Sharp, a secretive girl with an agenda against Serena involving her past. The second half of the season builds on the complications of Serena's new found relationship with her former teacher Colin, Chuck trying to regain control of Bass Industries from Russell Thorpe, and Dan and Blair's growing friendship. The season also focuses on Lily's past betrayals coming back to haunt her; Chuck and Blair's tumultuous relationship after their break up; Dan and Vanessa's deteriorating friendship; and the arrival of Serena's cousin Charlie Rhodes to the Upper East Side. By the end of the season, Blair has ignored Chuck, Dan has told Vanessa they are no longer friends, and Serena is on that single grind.

Welcome back, Upper East Siders. Summer is officially drawing to a close. Rufus, Dan and Jenny spent the summer in the Hamptons, adjusting to the van der Woodsen's glamorous lifestyle surprisingly faster than any of them expected. Blair and Chuck are madly in love and adjusting to their new "in a relationship" status. Nate returns from his travels with a mysterious brunette in tow. Serena returns from her European adventure with many secrets to hide as she gets ready to move into her dorm at Brown. Blair is determined to have her Queen status at NYU, along with Dan and Vanessa, but her roommate sets out to ensure that she does not retain her title.