The season opener finds Michael Scofield in Sona, a hellish and deadly Panamanian prison where a previous riot has forced all authority out and has left the prisoners in charge of their own lives (and deaths). With the fate of his loved ones hanging in the balance, Michael must to find Whistler, a mysterious fellow inmate hiding within the prison's sewer system, in order to break him out from a prison from which there is no way out. Meanwhile, Lincoln searches for a missing Sara and receives troubling news about LJ.

After Michael gets bad news from Linc, he sets out to find a prisoner named Whistler, who holds the key to his freedom. That's easier said than done: Whistler is hiding in Sona because there's a price on his head, and Lechero is not about to help Michael find him. In addition, both Mahone and Bellick want to get to Whistler too. Meanwhile, T-Bag won't allow a little humiliation stop him from insinuating himself into Lechero's good graces.

Someone slides an envelope containing a photo of Sara and LJ under the door of Linc's hotel room. It might contain clues to their whereabouts. The Company Operative in Panama City might help, too, but Linc must persuade her it's in her best interest to do so. And at Sona, Michael gets to know Whistler; Lechero begins to lose confidence in his ability to shape events; and Mahone, who is in increasing need of his medications, meets the lawyer who'll defend him.

After failing to rescue LJ and Sara, Linc receives an ominous warning from the Company; Michael plans an electrifying escape from Sona; a face from the past haunts Mahone; T-Bag crawls up the ladder while Bellick lands in hot water with Lechero.

A new inmate enters Sona, unnerving Whistler and raising Michael's suspicions; Linc plans an ocean getaway with Sofia as Susan moves up the escape timetable; T-Bag tempts his fate with his latest attraction; and Sucre attempts to get the goods into Sona.

Whistler becomes the prime suspect when an inmate is found murdered, leaving Michael to prove his innocence. Michael also wants proof that Sara is still alive or he will refuse to help Whistler escape. Meanwhile, Linc and Sofia watch the routine of the morning guards, and Mahone receives an offer to get him out of Sona.

Everything goes wrong for Michael as he tries to create a diversion. Lincoln tries to outsmart Susan. Sucre offers his assistance to Lincoln.

Susan takes the escape into her own hands; Lechero reveals a secret buried beneath Sona; Sofia uncovers more of Whistler's past; Mahone's freedom hinges on his testimony.

Michael hopes to talk his way out of solitary confinement, while Bellick gets himself into trouble after refusing to mop up a mess. Meanwhile, Susan B. has her sites set on Sucre as he makes a delivery to Sona. Sofia confronts T-Bag after he makes an offer to Whistler. Also, a mysterious American woman has arrived in Panama in search of Michael.

The battle for control of Sona comes to a boil between Lechero and Sammy as T-Bag enlists Bellick once again to display his fighting skills. Meanwhile, Michael returns to shore up the escape tunnel, and in Panama City, a search is performed by Linc on Gary Miller, while Sucre and Susan B. have a pair of meetings.

Lechero, Whistler, Mahone, Bellick and T-Bag all decide to follow Michael when he begins again to tunnel out of Sona, but working as a team may be a problem. Linc and Sucre assist when the weather causes some last minute changes in their plans. Back in Panama City, Sucre is threatened by Susan B. with the worst thing imaginable. She also longs to see Sofia again.

The escapees find success for some, if not all in their attempt, and are assisted by an unexpected source. But a mistake finds one escapee leaving behind something.

Michael and Linc meet up with Susan B. as the make their way into Panama City, minus Whistler. Meanwhile, Mahone waits at a Panama City cantina for an appointment, while a roadblock is setup on the way out of the country which stops McGrady and his father. Back at Sona, Sucre pays for attempting an escape, while T-Bag aids Lechero as he takes a look at the new landscape beyond the walls.