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.

The F.B.I agent Mahone decides to use L.J to get to Michael and Lincoln by cutting a deal with him and making him trick the two fugitives into revealing their location. Michael and Lincoln decide there's only one thing they can do, rescue L.J in a daring raid at the county jail. Only one problem though, Mahone is personally guarding L.J and won't let him out of his sight.

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.

Captain Bellick tortures T-Bag for the money during which T-Bag swallows the key and Bellick uses dirty tricks to get the key out.Bellick and Mac leave T-Bag on the boundary of the police.Sarah and Michael Scofield meet,but they are constantly chased by Alexander Mahone.Michael gets close to Mahone's helplessness.Meanwhile Lincoln Burrows and LJ are rescued by Lincon's dad but they are still not shielded from the dirty political games. Sucre tries to contact Maricruz but that plan fails because of the state police doing rounds.

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.

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.

Back at the yacht, Michael notices Lincoln is gone and calls him. Alex Mahone tells him Linc is no cold-blooded killer, so he was overpowered and hand-cuffed, and the ransom is the yacht and the fortune he assumes to be in it, to be agreed in five minutes. Now Mahone is even more wanted than the brothers. Kellerman's self-incriminating testimony and documents he brings get all charges against Sarah and Lincoln dropped, him arrested. Mahone calls Kim to fly over immediately. Alex calls his wife, to make her bring the kids for a holiday in her native Colombia, at Cartegena. Despite 30% blood-loss Fernado leaves hospital to report missing Bellick, who is already in jail and gets T-bag's company. Vendor Chaco gets Michael introduced to a local yacht owner to whom he suggests collecting the $100,000 reward on his head, then makes a better offer. Mahone called the police intending to frame the brothers for his intended murder on 'an Asian', but Michael refuses to hand over the money and Kim turns up early, with armed back-up. Mahone runs but is arrested. Kellerman knows the situation he is involved in and expects to be assassinated so his transport to prison is arranged to get car trouble and a masked man shoots him. Chaco delivers to the brothers, who got away with the money and intended to run and never look back, a crummy boat with a priceless surprise: Sarah and the great news for Linc, with good hope for Michael. Just then Kim turns up, refuses the money, aims at Linc and is shot by Sarah. Police arrive, chasing and trapping the trio. Michael takes the gun and pretends to take Sarah hostage, then lets himself be arrested and locked up in Sona. Malone calls his wife to forget he ever existed- from jail. T-bag expected to be released as agreed reward for baiting the brothers, but the man he hoped to bring him the good news says getting caught broke the deal.

Michael is once again imprisoned, but now in SONA (Panama), together with T-Bag, Mahone and Bellick. The prison is solely ruled by inmates, whose local prison-lord Lechero feels threatened by Scofield's 'fame'. Lincoln tries legal means to get Michael transferred, and gets a call from a relative. Both receive the same message, through different channels, from The Company.

After Michael gets bad news from Lincoln, he sets out to find a prisoner named James Whistler, who holds the key to his freedom. That's easier said than done: James 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.

Aftermath of Sara's death, Lincoln decides not to tell about it to Michael. Susan B. told Lincoln that if he does something wrong again, she's going to send pieces from LJ to him. Meanwhile, Sucre got a job in Sona. And Sofia starts to help Linc.

A test with a rat proves the tower snipers are very good, so Michael figures the only option to breaking Whistler out within 24 hours has to be at 3 PM, during the distraction of soccer game. Sucre accepts $5,000 from Lechero's cousin, Augusto, to smuggle a package into Sona. Linc is to arrange transport outside, but he and Sofia get turned away roughly by an army patrol two miles away. He tells her Sara has already been killed. He keeps it from Michael, as LJ is his ultimate priority. New prisoner Andrew Tyge is robbed to his boxers on arrival, and recognizes Whistler (who denies it), mentioning the McFadden, Nice in 1997. He is warned off by Mahone who has noticed Tyge snooping around Michael and Whistler. They plan an electric signal disturbance device to distract the guard tower. Before they can make a move, a reflection from the binoculars is spotted: the troops move in and find it in his cell. Michael admits it's his. When the commander is about to shoot him, Whistler claims it's his for bird-watching, and proves it showing the ornithology book (the one Linc couldn't hold on to).

Tyge tells Michael that he and Whistler were co-employees at the McFadden, a hotel in Nice, France. Mahone worries about Tyge's constant, keen observance of Whistler. Having to re-plan hastily, Michael tells Linc to find out the location of the nearby cafe and drug the guard's coffee, and also demands pictures of LJ and Sara before he escapes. Tyge is stabbed to death. Lechero questions McGrady and has Whistler dragged away for a confession. Michael believes Mahone and Bellick's denials. T-Bag offers Michael a ring he stole from Sammy (his rival for Lechero's confidence), to use to frame Sammy for Tyge's stabbing. Michael finds the murder knife under Mahone's bed and goes to Lechero to denounce Mahone, only to find he has just walked out of the prison. Agents Richard Sullins and Felicia Lang arrive at Sona to present Mahone with a plea bargain from the US Justice: a term reduction to 8 years for testimony against the government conspiracy and Lincoln. He could be out in 4 years, but Mahone refuses, now he faces life imprisonment. Lechero administers justice for Tyge his own way. Linc and Sofia succeed in drugging Captain Hurtado, but Susan finds out the brothers had a different timing planned and threatens LJ's life. With no recent pictures available, Linc confesses Sara's death, causing Michael to make a drastic decision.