It is the morning after their escape from Fox River, and the inmates narrowly avoid being caught by Bellick as they jump onto a freight train. FBI Special Agent Alex Mahone has been assigned to their case and calls a press conference urging the public to turn in the "Fox River 8." Michael, Lincoln, Abruzzi, C-Note, and Sucre encounter a hunter and his daughter. He holds them at gunpoint until Abruzzi grabs the daughter and forces the hunter to give them his SUV and let them go. The escapees head for a location where Michael has things stored. Agent Mahone tracks Michael's credit card to a storage facility in Oswego, but quickly figures out that one of Michael's tattoos holds the real location. Michael's tattoo "Ripe Chance Woods" is a clue pointing to a cemetery where Michael has items buried in the grave of "E. Chance Woods." Just two steps behind, Agent Mahone arrives at the scene just as the inmates have gathered what they need. In the meantime, T-Bag discovers a veterinary clinic and forces the Vet to re-attach his severed hand. Dr. Sarah Tancredi recovers from her overdose. Inside her purse, she finds an origami swan left for her by Michael with a message, "There's a plan to make all of this right", and a code. The code is a series of numbers which reads 3221243324 for the first line, 4221312231 for the second, and 23133121 for the third. Veronica locates Terrance Steadman in Montana, and finds that the doors are locked from the outside, holding him hostage (albeit willingly). Veronica calls 911, and then talks to Lincoln and tells him what she has learned. Employees of The Company arrive and kill Veronica for having unraveled their plot and for having found Steadman. Lincoln hears Veronica's final words as she dies, and is consumed with grief. Mahone studies Michael's tattoos, and feels that they are the key to finding the escapees.

With hospitals and clinics under surveillance, Michael brings Lincoln to Nika's home to heal his wounded leg. Then he returns to the place where he parked his Accord and finds that the car has been towed. Meanwhile agent Mahone retrieves Michael's backpack with his passport from a vagrant that broke the rear window of Michael's car to steal the backpack. Michael goes to Brewster Towing yard to recover his car. Meanwhile Sucre finds that Maricruz will marry Hector in a couple of days and he heads to New York in a stolen car. Sara is arrested and her father visits her, pays her bail and orders her to tell a fake version about the incident in Fox River since he will be the next Vice-President of United States. Later she goes to rehabilitation where Kellerman is pretending to be an addicted patient. C-Note schedules a meeting with his wife, but his conversation is bugged by agent Mahone. Bellick and Geary meet each other by chance and later they team-up to get the $400,000 reward for capturing Michael and Lincoln. They go to Fox River and Bellick interrogates Manche Sanchez, who discloses the plan of the fugitives. Michael and Lincoln forge a car accident to escape from Mahone, but they do not see that Bellick and Geary are in their tail.

Michael, Linc, and Nika are captured by Bellick and Geary, who intend to retrieve Westmoreland's money in Utah. Tweener continues his drive with Debra Jean. Abruzzi is reunited with his wife and children and is set to flee the country with them, but decides to take care of Fibonacci first. T-Bag has a close call with the police at a Nebraska gas station, and then poses as a Marine who lost his hand in Iraq. Mahone waits for confirmation of the deaths of Michael and Linc in the car explosion, and meanwhile gets a lead on one of the other fugitives. Kellerman (posing as a recovering addict named Lance) befriends Sara.

Michael and Linc arrive in Tooele, but the map they need to locate the double-K ranch is missing. They run into T-Bag and Tweener, who have also come to Tooele for Westmoreland's money. Meanwhile, C-Note makes his way by train toward Tooele. Sucre reaches Las Vegas and attempts to halt the wedding of Maricruz and Hector. Sara invites Kellerman to her apartment, believing he is harmless. At the FBI office in Chicago, Mahone reviews files recovered from Michael's hard drive, and begins to piece things together.

Michael's plan has hit a snag when the home owner's daughter, a cop, arrives. Mahone argues with Lyle Sands about how to proceed, but ultimately hopes that Tweener, in FBI custody, will reveal the location of the other escapees. Sara is now suspicious of Kellerman, so he tries something different to find Lincoln Burrows. In an Arizona detention facility, L.J. finds out he's to be released the next day; Linc drives to get him. Haywire, in Wisconsin, steals supplies from a camping shop.

In his efforts to try to get hold of all of the money Sucre runs into some unexpected difficulties. And Captain Bellick and his partner have not given up on finding their old inmates.

Michael tries to retrieve an item from Blanding Botanical Garden in Utah, but Mahone's people got to it first. Mahone believes that someone on his team is leaking information to the press; meanwhile Michael does some research on Mahone at an Internet café, then makes a trip to Durango, Colorado, to see a woman there. Linc and L.J. are on the road in Arizona. C-Note is in Chicago, and Agent Lang tries to use his wife to capture him. Bellick and Geary phone C.O. Patterson, at Fox River, to get information on where they should look for T-Bag. Sara is at a motel in Elgin, Illinois, trying to crack Michael's code. T-Bag arrives in Tribune, Kansas, for (as he puts it) "romance". Kellerman is on the trail of Sara.

In Maljamar, New Mexico, Michael takes what he needs from a sporting-goods store, then has a crisis of conscience. In Tribune, Kansas, T-Bag narrowly escapes the police but has to leave his hand behind. In Trinidad, Colorado, the three Burrowses discuss politics, but face an unexpected threat. In Gila, New Mexico, Kellerman ties up Sara and resolves to get what he needs from her. Mahone meets Kim for the first time. Bellick receives treatment for the blow to his forehead, and interacts with a local police detective.

Picking up from where we left off, Sucre, Michael, Linc, and Aldo are together, with Mahone on their trail. Sara is face-down in the bathtub as Kellerman prepares to dispose of her body. C-Note is in Harvey, North Dakota with Kacee and Dede, who needs her medication. In Tribune, Kansas, Detective Slattery questions Bellick.

The Border Patrol arrests Michael and Lincoln, saving them from Mahone that claims that wants his life back. Sucre crosses the border and jumps in a parachute in the Sonora Desert in Mexico. T-Bag goes to a war veteran bar in Pratt, Kansas, and steals a prosthetic job from a veteran sergeant. Michael and Lincoln are apprehended in the Border Patrol Holding Facility, in Las Cruces, New Mexico, waiting for transportation to Fox River, but Bill Kim orders Mahone to kill them. T-Bag meets Denise, who works in the post office, and seduces her to get Susan Hollander's address. Bellick is sent to the District Court in Greeley County, Kansas, and has his bail denied. He makes a deal to be sent to Fox River expecting to have a good life. However the new warden decides to use him as an example of the new administration. Meanwhile Mahone tries to transport the prisoners, but the standard procedure does not allow it. Kellerman makes an arrangement to intercept the convoy in a blocked tunnel to kill the prisoners. However, Michael and Lincoln and helped by a surprising allied. T-Bag finds Susan.

Linc and Michael have decided to take the keys and escape, figuring at least they'll go down fighting. FBI Special Agent Alexander Mahone chased them while staying in contact with Secret Service Special Agent Paul Kellerman who suddenly shot Mahone and gave the brothers a ride because he wants revenge on the White House; Linc wants his instead, but is offered the location of Terence Steadman. T-bag visits his ex-girlfriend, who tells him the children think he's their Uncle Teddy on an oil rig, but he moves in; when she goes for a gun, he attacks her and her son attacks Zach him, so he turns the home into a private prison. In prison, former boss Bellick, who naively had made a deal in order to do his time in Illinois, shivers in general population among the prisoners he abused and their mates, he has none as the new warden sees him as an example of his new, clean ship; he soon realizes there's no pleasing them, and tries hitting hard; a loyal guard warns him the night shift is on his enemies side as he treated them badly. Benjamin Miles 'C-Note' Franklin tries to save his Kacee who is in custody, advising her to put all the blame on him; after hearing how scared his girl is, he asks one of his friends for help to run while she's on bail but the judge refuses bail. Mahone awakes in hospital, and reports to Kim on Kellerman's betrayal and the brothers' escape, which is hitting the TV news, but refuses to play anymore, even if that means jail; when his wife Pam phones their son is hurt he rushes out for Colorado, but is stopped to hear it's a warning to force him back in line; however he is through doing Kim's bidding and shoots his man. Kim calls Steadman's bodyguards: he must be evacuated to a safe house as Kellerman knows his residence, but he is already there with the brothers- Kims orders to kill everyone, but only the FBI men are shot; Kellerman explains Steadman is made unrecognizable, including plastic surgery, so their only option is to get him to Washington, where FBI agents who know can still make the truth stick. Michael decides instead to turn himself in while informing the press, despite Kellermans gun aimed at him, but Steadman prefers to commit suicide, and his corpse is worthless for the brothers.

In Cutback, Montana, Kellerman lures the police and Michael and Lincoln abduct the cameraman Greg of Fox News and succeed in escaping from the siege. Michael and Lincoln decide to tape a message to be released in the Breaking News. Mahone is back in Chicago and analyzing the message; he interrogates Greg and he tells that he had overheard Michael tell that they should cover 460 miles in six hours. Mahone deduces that they intend to meet President Caroline in Denver. Wheeler discusses with Mahone and yells that the Internal Affairs department asked him to follow all moves of Mahone. Bellick is badly wounded in the infirmary of Fox River. Sucre befriends an old passenger in a bus to Ixtapa; however the driver asks him to leave the bus in a small town and Sucre robs the Volkswagen of the old man. In Algoma, Winsconsin, Haywire befriends a young couple and the girl has bruises on her arm; she tells that her abusive drunken father beat her.

Sara meets Michael and Lincoln in a train station in Evansville, Indiana; when she sees Kellerman with them, she becomes disturbed and upset. Kellerman tells that she has a key of a private cigar club in Chicago. Caroline calls Kellerman and he tells that he is heading to Chicago by train, and she promises his life back, inclusive the chief of staff position. T-Bag tells Susan that they are passing through an "adjustment period" in their lives; when she tells him that she will have a guest called Patty Wallace, T-Bag welcomes Patty with a magnificent family brunch and uses the strong father figure to discipline Zack, seducing the guest with his charm and attitude. Wheeler is reporting the actions of Mahone to the FBI Headquarter and they find that Haywire killed a man in Algoma, Wisconsin. Mahone visits Bellick in River Fox, releases him using a habeas-corpus to make his dirty work, and gives a car, a pistol and an FBI badge to the despicable man. Bellick chases and traps Haywire, and waits for Mahone. In Benson, Minnesota, C-Note and Dede are leaving a snack bar when an addicted thief announces a heist. When Kellerman sees a road block on the train, he realizes that he was betrayed.

Michael Scofield and Sara Tancredi fail to get the tape from the Corona de Oro cigar club in Chicago, where security was at the ready, and turn to former warden Henry Pope, a club member, but he wants to call the police. Michael draws his gun and hands it over to prove his veracity; Sarah convinces him to go in with her late father's humidor key and he finds a computer memory stick. In Mexico, Fernando Sucre has car trouble and gets a ride from an Ixtapa airport security employee who sees his wanted-poster just after they parted at the airport, so he must run with his bride. T-bag and his forced-along family find his own house vandalized and looted except for the family bible, which arouses in him youth memories of his perverted father, and assures Suzy he wants their love and is happy to be infertile, her bloodline should take the Bagwells's place. When she refuses, he locks them up, considers ax-murdering but just leaves them behind. FBI Special Agent Alexander Mahone has tracked down Benjamin Miles 'C-Note' Franklin and his daughter, but lets them escape in a bus rather than shoot the kid. C-Note brings her to a doctor, worried about the kidney disease PKD, but won't allow inserting a catheter, rather turns himself in to Mahone, who is with his own boy in Colorado, and makes a deal to get him Scofield. Pope is out of the club, but is greeted at the entrance by Secret Service Special Agent William 'Bill' Kim whom only Paul Kellerman, watching from a roof with Linc, knows by sight. Michael drives over Kim and gets away with Pope, Sarah and Linc, locking Kellerman out. When Michael tells the others he's prepared to honor his promise to Pope (which the others didn't know about) to turn himself in for his help, Henry hands him the stick and lets them go.

C-note has jumped with the noose around his neck, but is saved by jailers; he has Mahone told he'll still do it. At a Chicago hotel, president Caroline Reynolds is expected for a speech. Michael sends the real Cooper Green away and agrees a meeting point with Linc and Sarah. Mahone enters Sarah's room and only pretends to fail looking under the bed to trap her, she pretends the brothers left her. In Mexico, T-bag finds Bellick is waiting at the luggage conveyor and must get his from the service side, but the laborer he knocks down falls onto it, so he must run. Lincoln surprises his old mate Derrick Sweeney and calls a favor: three tickets on a freighter for Panama. Kellerman is in position to shoot the fiendish president, but when she's in his sight Michael gets arrested just after shaking her hand, and is interrogated by Kim who demands to be left alone with him, to ask where Linc is, then tries literally to beat it out of him; the president barges in and sends Kim out just when he was about to shoot Michael; he tells her the tape is a delicate conversation she had with her brother after his 'death', and he still has copies at twenty locations. Fernando sees on TV T-bag is in Mexico and was videotaped trying to steal, so he deduces the $5,000,000 must be around and tells Maricruz he'll be right back; at his return only Bellick is there, armed and cuffs Sucre, in order to collect the reward, so Fernando offers to share the $5,000,000 by finding T-bag. Sarah guesses right Mahone is on an addictive drug. Caroline calls Linc, who plays the tape which proves her brother was alive on the isle of Terrence and hated conspiring with her Linc's faked conviction; Michael tells her about his suicide and dares her to make a decision: let him walk and sign a pardon for both brothers the very day, on live TV; Kim fails to stop him being released and walking out. When the phone rings, Sarah surprises Mahone and escapes- actually he arranged this and has her followed. Kim talks to a grim man in power; Reynolds announces on TV she has a malignant cancer and resigns immediately.