It's been one year since the 4400 returned. After a period of intense medical observation, Tom has returned to NTAC in a limited capacity, assigned only to desk duty. Diana, having been through a series of inept partners, finally finds a way to cut through the red tape and get Tom back, all while in the midst of formally adopting Maia. Meanwhile, Richard, Lily and the baby are still living in meager conditions in a mountain cabin far away from Jordan. Jordan has now closed Arcadia Estates, and is on the verge of opening 'The 4400 Centers', a place for non-members of the 4400 to discover 'the 4400 within themselves'. Collier becomes Shawn's guardian, and enlists him to heal important benefactors of the Centers.

It's been one year since the 4400 returned. After a period of intense medical observation, Tom has returned to NTAC in a limited capacity, assigned only to desk duty. Diana, having been through a series of inept partners, finally finds a way to cut through the red tape and get Tom back, all while in the midst of formally adopting Maia. Meanwhile, Richard, Lily and the baby are still living in meager conditions in a mountain cabin far away from Jordan. Jordan has now closed Arcadia Estates, and is on the verge of opening 'The 4400 Centers', a place for non-members of the 4400 to discover 'the 4400 within themselves'. Collier becomes Shawn's guardian, and enlists him to heal important benefactors of the Centers.

Gary Navarro, a minor league baseball player back after a 30-year absence, finds that hearing everyone's unspoken thoughts is driving him to the edge of madness. When he seeks help from NTAC, the higher-ups are more interested in how he can unearth information about Jordan Collier than how they can assist Gary with getting his life back. As the case occupies the majority of his time, Tom finds himself struggling with his responsibilities as a single father. Meanwhile, Kyle starts to get his life back through the prospect of a new relationship, Diana finds herself dealing with the unexpected arrival of her younger sister April, and as Richard, Lily, and Isabelle continue their life on the run, Richard grows increasingly disturbed by his daughter's apparent abilities.

Someone puts his 4400 ability up for auction, and the Supreme Court will have a special session to determine if it's legal and if the auction can continue. Diana and Tom are ordered to investigate. Meanwhile, pop diva Chloe Granger is at the 4400 Center and claims that Jordan's book was a revelation to her. She even cut her tour short because she felt she needed to come to the 4400 Center and become a student. Jordan makes sure this new 'recruit' is well treated as it will profit the center. Shawn is working on a recruitment video for the 4400 Center. Richard and Lily travel to Montana where they meet with Eric Papequash, who disappeared in 1955.

A school teacher terrifies parents with her supernatural ability to inspire artistic students. Meanwhile, Richard and Lily are confronted by police, and Jordan warns Shawn not to overuse his healing gift.

Maia's morbid premonition threatens the fate of Jordan Collier. Kyle's frightening blackouts are disrupting Tom's personal life. Diana is asked to hand over Maia's diary to NTAC.

Tom and Diana track down a man to a museum, and during the chase, Tom finds a mysterious lab that only he can see. Later at the office, Tom finds that all his 4400 case files are gone, and no one has ever heard of the 4400.

Tom and Diana investigate a 4400 who has released a plague that's wiped out an entire town's population, and her powers could wipe out humanity. Meanwhile, a Washington D.C. lobbyist joins the 4400 Center in order to add some political muscle to the movement. Also, April uses Maia's powers to win gambling bets.

A male 4400 originally from Rwanda repairs bad chromosomes of unborn. Kyle is utterly despaired as he suddenly remembers what he did during his blackout. Rishard attends a co-veteran's funeral. Diana takes s hard family decision.

NTAC follows a series of clues which leading them to Jordan Collier's hugger, and when Tom discovers Kyle was the cuddleer, he must choose between the law and his family. Meanwhile, at the 4400 Center, Danny stirs up a mess with Liv - as well as with his brother Shawn in the process.

On Jordan Collier's birthday, an unknown 4400 releases a 'rage bomb' at NTAC, causing all the male agents to revert to their primal instincts. In order to stop the spread of the behavior, NTAC goes into lockdown, sealing all personnel inside. Now it's up to Diana to find a cure and stop the carnage before it's too late. Meanwhile, Lily suspects the 4400 Center may have nefarious motives toward Isabelle, Shawn adjusts to being the figurehead of the 4400 in the media spotlight, and Kyle finds the prospect of a new romantic relationship.

The authorities led by Dennis Hyland wants to quarantine every 4400, as several of them are sick with the same as Maia. Hunted by bad conscience Kyle somehow contacts Marsden's girlfriend.

On the heels of discovering that NTAC is behind the disease plaguing the 4400, Tom and Diana find themselves enveloped in a government conspiracy to hide the truth. Although the disease was an unforeseen side affect of an inhibitor secretly administered to the 4400 to prevent the emergence of special abilities, it's clear that the powers that be are more concerned with covering their tracks than curing the disease. Now Tom and Diana must face off against their own agency as they race against time to get to the bottom of NTAC's coverup and help find a cure before it's too late.