Charlie accurately predicts where a band of bank robbers will strike next. But when Don and his team confront them, a massive shoot-out occurs leaving four people, including an officer, dead. The outcome disturbs Charlie and he retreats into the family garage to work out an unsolvable math problem that he also plunged into after his mother became ill a year earlier. But Don needs his brother's help and tries to get Charlie to return to the case.
Various people in the L.A. area with seemingly nothing in common start to become extremely sick and die on the same day. Don fears bioterrorists may have released a deadly virus into the environment. While he tries to discover whether anyone is behind the outbreak, Charlie tries to locate the point of origin.
After an engineering student at CalSci is found dead from an apparent suicide, Charlie convinces Don to launch an investigation after he reads the student's thesis that asserted that the architecturally magnificent Cole Center in Los Angeles is structurally unstable. Although reluctant at first, Don and his FBI agents discover that the student's findings were correct and uncover a dangerous and surprising conspiracy. Meanwhile, Alan prepares for a first date and convinces Don and Terry to join them, hoping they might rekindle their old romance.
When a five-year-old girl is kidnapped from her birthday party, Don and Terry lead the investigation, but must rely on Charlie's help because the girl's father, Ethan, is also a mathematician. Charlie realizes the kidnapper's motive when Ethan reveals he is close to solving Riemann's Hypothesis, a difficult math problem. If solved, the solution could not only earn him $1 million, but could break the code for internet security and unlock the world's biggest financial secret.
While consulting with the NTSB at the scene of the wreck, Don learns that this tragedy is one of a series of recreated accidents involving railroad negligence. As is the pattern with the previous train wrecks, an undecipherable numerical code is left at the site, which Don recruits Charlie to solve. By breaking the code, Charlie is able to establish that this accident was a recreation of a deadly wreck that left only one survivor several years ago. Don's investigation leads him and his team to a dangerous standoff with their suspect, who has surprising ties to the railway system.
Don learns that counterfeiters are at work producing small-denomination bills, and that they have taken an artist hostage to draw the images for the fake money. If the missing woman isn't located soon, Don fears that she will be killed when her work is finished on the phony cash. The counterfeiters have already murdered at least five people, two of whom stole money from them. The case is made more difficult for Don when his former lover, now a Secret Service agent, is assigned to it.
A man wanted for stock fraud is found garroted in his apartment, and the crime is eerily similar to a murder committed a year earlier, a case in which Don closed when an ex-con confessed. Now, Don must re-investigate the old case to determine if he put an innocent man in jail. He asks Charlie to go over the evidence to see if he missed anything the first time around.
A truck carrying radioactive material is stolen, and the thieves threaten to set off a dirty bomb in L.A. in 12 hours if they aren't paid $20 million. While Don attempts to track down the truck, Charlie tries to come up with the most likely location where the bomb may be detonated to inflict the most damage to the population.
A senior computer-science researcher working on a classified government project is found murdered in his Hollywood Hills home and data has been stolen from his computer. The investigation reveals the victim was going through a bitter divorce and was trying to keep his wife from getting his money. Charlie also learns the project on which the man was working might have involved baseball.
Don and Agent Weston of the NTSB investigate eyewitness accounts of a mysterious unidentified object flying dangerously close to downtown Los Angeles that has raised concern of a terrorist attack. After Charlie is recruited to help with the investigation, it is discovered that the flying object is part of a new technology that could revolutionize air travel. But the investigation takes a turn when they learn that the lead engineer is found murdered.
A dangerous felon escapes when a prison bus crashes and the FBI has reason to fear he's intent on revenge against the witness whose testimony put him in jail. However, finding the elusive killer proves to be a complicated challenge. Don teams up with Agent Billy Cooper, his former partner from the FBI's Fugitive Recovery Division, and Alan worries that Don's going to return to a more dark and obsessive time in his career.
Don and Charlie investigate the murder of a judge's wife who was shot in her garage. It's unclear whether she was the intended target or her husband, who was hearing a death penalty case involving a gang leader. As the investigation continues, Don reconnects with a prosecutor whose life may also be in danger.
The FBI becomes involved in the stalking of a popular singer after she is threatened by an intruder in her house and reveals a series of threatening letters she's received through the mail. Charlie determines the letters are from two different people after analyzing the handwriting. When a photographer is found dead near the singer's house, Don believes the photographer was murdered and his death is somehow related to the stalking case.
Don and Megan are called to the murder scene when the CFO of a powerful energy company - who was about to testify against her fellow executives - is murdered at her home and her son is the only witness. Knowing there could be thousands of disgruntled ex-employees, Don asks Charlie to narrow the list.
Megan feels responsible for an agent's death following an explosion at a meth house the FBI had targeted for a bust. When the kingpin eludes capture, it's discovered he may also be involved in child pornography when one of the photographs on his computer turns out to be a young girl in a sexually explicit position. The picture sends Charlie on a crusade of his own, as he remembers a girl he knew as a young child that he suspected was being abused, and he's determined to save the little girl in the picture.
An arsonist sets a fire at a car dealership that kills a sales person. The name of an extremist environmental group is spray-painted on the scene, but the group denies involvement. It becomes Don's task to determine whether the group or someone else is responsible. Charlie is called in to help figure out if there is a pattern to the fires that would help provide a profile of the arsonist.
When an Asian teenager is found in the basement of an old downtown hotel where she was apparently being tortured, the investigation soon reveals the girl and three other missing women, are victims of a black market organ-harvesting scheme. Amita assists the FBI by communicating with the girl, who is from the same part of India where Amita's family once lived.
Don and his team investigate an anti-war bombing outside an Army recruiting center that resembles the work of a 1970s anti-war activist who disappeared 30 years earlier after being accused of planting a bomb that killed two people. Retired Agent Thomas Larson, who tried to solve the case 30 years ago, returns to help but questions Don's loyalty when it is revealed Alan knew the radical activist and participated in demonstrations with him, thus causing tension within the family.
Don and his agents are asked to investigate when a search team finds three dead women in the wilderness who were apparently murdered under bizarre circumstances. The case becomes more suspicious when Don learns the search team was led to the crime scene by a psychic. When the psychic offers to help the FBI in solving the crime, Charlie is determined to prove the psychic is a fraud.
In an effort to find the murderer of an Iraqi woman who had been making a documentary that promoted the rights of Muslim women, Don enlists the help of the victim's cousin. Through her cousin, Don uncovers a connection to Saddam Hussein. Back at home, Charlie rekindles a romantic relationship with a former girlfriend when she visits him while on a book signing tour.
Don and his team investigate a school shooting. He learns two students could have a strong motive, so Charlie uses the school's radio frequency identification system to track the shooters' movements through the school's hallways. When Charlie detects an abnormal pattern, the agents take a look at the evidence and discover a third participant no one had suspected earlier.
When an ATF agent is found dead under unusual circumstances, Don wants to take the case, which revolves around an elaborate bank robbery, after he learns the victim was his former girlfriend. He then becomes quite introspective as he realizes the impact his career has had on his personal life and decides to turn his attention toward a new woman.
The FBI becomes involved when the bodies of young Asian girls are washed up on the beach. The situation becomes more critical when it is discovered one girl has avian flu. As the investigation continues, Don and his team discover a connection between the girls and the sex trade industry. Meanwhile, Amita considers a transfer to Harvard University, which causes Charlie to re-evaluate his feelings for her.
Don investigates the murders of two young women found in their cars outside their homes. Their deaths were made to look like drug overdoses, but Don realizes a serial killer is responsible. Meanwhile, Charlie is having bizarre dreams about his parents. In one dream, his deceased mother appears and tells him he has a question to ask her, but he can't imagine what it could be.
A California State Senator and a psychiatrist--neither have much in common with the other except for one thing...they both turn up dead on Don's watch. While the circumstances of their deaths are different, Don thinks the two murders are related, and tries to prove his hunch right. What he finds may bring to light a deep secret the government has been hiding for years.
The team attempts to find the daughter of a geneticist who they suspect was kidnapped by the unstable mother. However, they become concerned about the case when they find evidence that suggests the young girl was a clone. Meanwhile, Charlie and Amita discuss having kids and Liz reveals a dark secret.
When the team foils a robbery of an armored car full of Federal Reserve money and recover bills that trace back to the infamous D.B. Cooper heist, they call on Agent Roger Bloom, who worked on the Cooper case, for help with the investigation. Henry Winkler returns as former FBI Agent Roger Bloom, and Michael Hogan, the uncle of the slain armored car driver and a key player in the investigation.