Three years have passed since the events of Day Two. A van deposits a dead body outside the LA Health Unit. The body is infected with a deadly virus. Tony, now in charge of CTU, learns that this is a blackmail tactic to get the US government to release a drug lord, Ramon Salazar, whom Jack has just brought down, before Salazar's brother releases the virus into LA. Jack and his new partner, Chase Edmunds, prepare to sign a deal with Salazar at the prison. Salazar delivers a mysterious warning to Jack before killing his lawyer. Palmer is alive and well, and has returned to LA for the first time since the attack three years ago. He is running for re-election and is preparing for an important debate with a rival senator. He is accompanied by his brother, who happens to be his chief of staff and his doctor, who also happens to be his girlfriend.

Jack and Chase quarrel over Chase's relationship with Kim. Meanwhile, they learn of a lead to the possible whereabouts of the virus after raiding a crack-house. Linda breaks up with Kyle when she learns that he is planning to make a drug delivery. Wayne approaches Palmer with information about his girlfriend that could damage his chances for re-election, while a CTU employee is not what he seems.

Jack and Hector both search for Kyle, while Chase finds himself out of action at CTU. Wayne and Palmer argue over the implications of Anne's past, while Ramon takes out one of his opponents in a surprise move. Tony leads an operation to get Kyle, but tragedy strikes when Salazar's man gets there first.

Michelle is torn by personal and professional obligations when she must take charge of CTU after Tony is wounded. Kyle and Linda are captured by Hector's men. Jack and Palmer have a secret conversation, leading Jack to take drastic action in the face of the Salazars' threat. But Jack's plans are complicated when Chase gets in the way. Anne pushes Palmer back onto moral ground in the face of her ex-husband's blackmail scheme.

Jack's efforts to break Ramon out of prison go awry when they are captured by a group of inmates during the riot. Chloe unwittingly stumbles on to Jack's drug problem and she is forced to reveal his secret to Kim and Michelle. Palmer begins his debate with Keeler, while Kyle prepares to sacrifice himself to save Linda.

Jack and Ramon struggle to evade the authorities, while Palmer must shut the debate down because of the prison break. Kim accidentally stumbles on to Gael's secret communications, but she isn't able to warn Michelle in time. The Singer family learns a startling piece of news about Kyle's health.

Ramon holds Jack hostage as he flies to Mexico. Ramon plans to kill Jack, but Jack manages to hold him at bay until the plane lands. Ramon then learns that Jack and Hector are working together to break him out of prison. Gael is captured while trying to escape from CTU. Chappelle interrogates Gael but is interrupted by Tony, who claims that Gael is part of a bigger plan. Anne is given a chance to clear Palmer's name, while Chase heads for Mexico to rescue Jack.

Palmer and Chappelle view a message from Jack, explaining his undercover work with the Salazars. Meanwhile, Hector tries to convince Ramon that they should deal with Bauer so that they can get their hands on the virus. Jack has a private moment with Claudia and she blasts him for leaving her behind when he arrested Ramon. Chase arrives in Mexico, but is captured by Hector's men. Ramon devises a way for Jack to prove his loyalty to them. Anne manages to clear Palmer's name, but she breaks off her relationship with him.

Palmer clears Anne's name with the press, but he finds that he is facing a new problem when his biggest campaign contributor reveals a startling secret about Wayne. Kim and Michelle worry about Tony's mental ability when he continues to make mistakes. Jack and the Salazars meet with Amador, but the deal turns sour when Nina Myers appears on the scene and competes for the virus.

Claudia manages to free Chase from his captors, but she pays a high price for her efforts. Wayne turns to Julia, while Palmer calls on Sherry for help against Milliken. Jack and Ramon make plans to get to Nina, in the hopes of intercepting the virus. Chloe's work at CTU is disrupted when she is forced to take care of her baby.

Jack forces Nina to work with him to get the virus from Amador. Palmer meets with Sherry and convinces her to help him deal with Milliken. Chase remains in Mexico to help with the capture of the virus. Ramon and Hector quarrel when Hector wants to pull out of the deal.

Things finally come to an explosive head as Jack, Ramon, Nina and Chase all close in on the virus. But the deal takes an unexpected turn when Amador pulls a fast switch. Kim becomes suspicious of Chloe when her story about her baby doesn't check out. Sherry finds a witness who can damage Milliken, but her advantage is short-lived.

Jack and Chase interrogate Nina, but the worm turns when she causes havoc with the CTU computer systems. Chappelle puts Chloe under guard when she refuses to answer questions about the baby, but is forced to release her when she is the only one who can deal with the crisis. Sherry takes her battle directly to Alan, forcing Julia to act as her accomplice.

Tony interrogates Nina about Alvers' location, while Chappelle orders Jack to undergo a medical examination in light of his drug use. Kim and Chase have a conversation about the baby. Palmer confronts Sherry about Alan Milliken's death, while Julia begs Wayne for help.

Chappelle threatens to pull Jack from the investigation for killing a material witness, but Jack persuades him to hold off when they find a fresh lead on Amador's whereabouts. Amador and Alvers meet with the man who is planning to unleash the virus in LA within the hour. Michelle and Gael locate the target area, but things really hit the fan when they attempt to capture Alvers in the process of releasing the virus. Wayne argues with Sherry over the consequences of Milliken's death as the police turn up the heat on Julia.

Jack and Chase track Amador in the hopes that he can lead them to the man behind the virus attack. Michelle faces a mob riot when the hotel is quarantined. Sherry extorts Palmer, forcing him to manufacture her alibi for the police.

Saunders begins making demands on the President. He forces Palmer to hold a strange press conference and then orders the death of the CTU agent who can trace him. Jack learns of a woman who can lead him to Saunders, but a surprise attack shifts the balance of power. As Gael's symptoms get worse, Michelle devises a way to relieve the suffering of the victims at the hotel.

Jack and Chase race against time to capture Saunders before the deadline, while Chappelle plans an escape. Michelle begins a frantic search when she learns that an infected hotel guest may have slipped through her fingers.

Jack reluctantly works with Kim on an undercover job that may help them gain an advantage over Saunders. Palmer informs his cabinet of the crisis, while Saunders makes yet another demand. Chase tracks down the man who left the hotel and learns that the virus is spreading to the general public.

Tony works to free Jane from CTU before Saunders can harm Michelle, but Chloe and Jack become suspicious of his activities. Sherry meets with Palmer's political rival and proposes a deal to blackmail him.

Jack and Tony clash as the time for the hostage exchange draws near. Keeler meets with Palmer and demands his resignation, while Wayne begins a secret operation against Sherry.

Jack pushes the envelope in an attempt to force Saunders to disclose the location of the missing vials. Sherry meets with David to discuss her terms, while Wayne breaks into her home to find the incriminating evidence. Tony finds himself facing a harsh penalty because of his efforts to save Michelle.

Jack and Chase must make a powerful sacrifice when dealing with the virus. Tony is able to help Jack one last time before he is taken into custody, while an angry victim seeks vengeance on Saunders. Palmer makes a surprising career choice in the wake of Sherry's death.