After engineering a daring escape from the hellish, Panamanian prison Sona, brothers Michael Scofield and Lincoln Burrows are determined to seek justice against The Company, the shadowy group responsible for destroying their lives and killing the woman Michael loves, Dr. Sara Tancredi. Michael’s quest for vengeance leads him to Los Angeles, where his world is turned upside down when Company operative Gretchen/Susan B. Anthony informs him that Sara is still alive. Realizing the only way they will truly be free, Michael and Lincoln avow to find Sara and take down The Company. With the help of Homeland Security agent Don Self, they assemble a group of allies and familiar faces to accomplish their task: Mahone, Sucre, Bellick and computer expert Roland Glenn. Unfortunately for the brothers, they must also evade company assassin Wyatt and find an on-the-loose T-Bag. Michael and Lincoln soon discover the only thing harder than breaking out will be breaking in.
Michael has trailed Gretchen/Susan, Whistler and Mahone to L.A. Chaos reigns in SONA while T-Bag, Bellick and Sucre go missing. Lincoln and L.J. continue to stay with Sofia.
Michael, Lincoln and the others get a new team member, Roland, and work to copy the data card. Wyatt continues his quest to find the brothers. T-Bag makes his way north.
Michael attempts to track the cardholder and avoid going back to prison. Wyatt finds new information regarding Sara's whereabouts. Elsewhere, T-Bag uses a new identity to make a new life for himself.
Michael, Lincoln and Sucre must crash a police benefit to obtain the next card key. Reeling from another death, Sarah falls back into an old habit. T-Bag arouses suspicion and runs into some old “friends” his first day on the job.
Self locates another card hidden in a safe within a secure federal building, as Mahone continues his quest for revenge. Meanwhile, T-Bag's new life may be in jeopardy.
The entire operation may be in jeopardy when Mahone gets into trouble with the law. Gretchen's sister receives a surprise visitor. The Company may be onto Self. T-Bag continues to raise suspicions at Gate.
Lincoln takes members of the team to Las Vegas where Sucre gets an indecent proposal. Sarah learns about Michael’s condition, and Roland pushes his luck too far. Gretchen teams up with T-Bag who makes an offer to Michael he cannot refuse. Meanwhile, the secrets in Whistler’s bird book are finally revealed.
Lincoln works to retrieve the final card, which is being held by the General. Michael and Self are forced to work with Gretchen. Meanwhile, Roland continues to be berated for losing the transcribing device in Las Vegas.
Wyatt gets a taste of his own medicine, and Mahone finds some resolution. T-Bag scrambles when the police investigate his missing co-worker while Gretchen gets cozy with a Company man. Meanwhile, Michael’s condition continues to worsen, and a team member makes the ultimate sacrifice while planning the underground break-in for Scylla.
Sara is left with no choice but to take Michael to the hospital as his condtion rapidly worsens. Sucre and Lincoln are faced with unknown territory as they are left in charge of the operation. Elsewhere, agent Self makes a surprising ally.
Michael races against time and his ailing health to break into the Company headquarters to steal Scylla, but the break-in’s success lies with Sucre. Gretchen dresses up for a meeting with the General and one final attempt to get the last card key. T-Bag must make a decision to leave his criminal ways for good.
Sara takes a hostage in a bid to secure Scylla. In the meantime, Michael and Lincoln finally meet the General while one of their members switches allegiance.
It's up to Michael to hold the gang together after they find out they were betrayed by one of their own. Meanwhile, Gretchen is blackmailed by T-Bag's new partner.
Michael, whose condition is deteriorating, winds up in the hands of The Company who promise Lincoln that they can save Michael's life in exchange for a favor. Elsewhere, Gretchen and Self wind up with Scylla and a buyer.
Lincoln and his new partners arrive in Miami to recover Scylla from its shocking new owner, and Sara searches for a missing Michael who learns some surprising information about his past. Meanwhile, a double-crossing leads to a death and an arrest in "The Sunshine State."
Michael and Sara journey to Miami while Lincoln meets with his mother. T-Bag and Self's mission to locate Scylla takes a dramatic turn. The General comes under pressure.
Michael and Lincoln come to blows over Scylla as Christina sets the wheels in motion for her plan. Meanwhile, Sara receives life-changing news. T-Bag arrives at the Indian Embassy. The General becomes increasingly paranoid.
Michael's reunion with Christina is soured when she drops a bombshell regarding Lincoln, and T-Bag grows determined to prove he is worthy of being a member of the Company.
Pandemonium erupts at the hotel following the assassination, and Christina puts the final pieces of her plan together. Meanwhile, the General makes good on his threat, and Michael is forced to choose between saving either Lincoln or Sara.
Familiar faces return to help Michael end his quest to bring down The Company once and for all.