C. J. Cregg begins her tenure as White House Chief of Staff, as Toby and Donna begin searching for a new Press Secretary. The Republic of Georgia offers to give the United States its stockpile of weapons-grade uranium. Josh meets with Representative Matthew Santos of Texas, who is retiring from Congress despite having only recently been elected to his seat. Santos will become a recurring character this season, as he begins a campaign for the Presidency.

While Rita and the kids are out of town for a wedding, a police officer comes onto Dexter's radar. The officer is a kindred spirit, and highly suspicious of Dexter's motives. LaGuerta and Angel discuss full disclosure to the police department leadership about their relationship, pulling Dexter unwillingly into the middle of their problem. Meanwhile, Quinn's reporter girlfriend, Christine, uses their relationship to put out a story how Lundy's hunt for a phantom killer pulls time away from the Vacation Murders. This puts a strain on Lundy's retirement project when his visitor's pass to Miami Metro is revoked. Having to take the project out of the office, old sparks heat up between Lundy and Debra. At the end of the episode, Lundy and Debra are shot by an unseen assailant.

In the season finale, Dexter's situation grows desperate when he discovers that Lumen has been set up. Despite knowing he is being baited into a trap, Dexter risks everything to save Lumen from the murderous Jordan Chase. In the Barrel Girls case, Debra lets her personal feelings lead her instincts once she concludes that vigilantes are more than just a theory. Debra closes in on Jordan after receiving a tip about his whereabouts.

The hospital buzzes with rumors of House's upcoming date with Cameron. After House is harsh to an awaiting clinic patient (John Cho), the man develops a mysterious stroke. At the same time, House also deals with an elderly couple whose overactive sex life is seemingly causing them problems.