It's an ordinary day off for Tom Baldwin, until Diana shows up at his house to arrest him for murder. It seems that earlier that morning Tom entered an NTAC interrogation room and shot T.J. Kim. But Tom hasn't been in to work yet and has no recollection of the event. Tom goes on the run to find the truth. It's eventually discovered that a teenage 4400 recruited by Nova, was sent to kill T.J. Kim. Gelder's ability allows him to make people percieve him as any identity he chooses. In the end, he is apprehended. At the 4400 Center, Shawn helps Isabelle catch up on some of the milestones she missed from growing up overnight. But Shawn soon learns that Isabelle's list includes sleeping with him. Shawn is hesitant since he promised Richard that he would be only a friend to his daughter. In the end, Shawn gives in to temptation. Meanwhile, Diana discovers that Kevin Burkhoff, who has been injecting himself with doses of promicin, has developed a 4400 ability.

When the future abducted five 4400 children, Maia included, and re-seeded them back into the timeline, they erased the children from the memories of anyone who knew them. Despite the future's efforts, Tom and Diana began to recall the children being abducted. Tom and Diana were able to locate, in the pages of history, where and when some of the children were sent. In all cases, each child helped bring forth some advancement for humanity. Diana enters an alternate reality, through Alana's ability, to spend time with Maia. Knowing she will never see the real Maia again, Diana decides to stay there. The mental strain of staying there for an extended period of time could result in death in weeks. Knowing he's a part of the future's plan, Tom attempts suicide inside one of Alana's altrnate realities with the hope that the future will intervene and grant him an audience. After much debate, the future forms a deal with Tom. In exchange for returning the children, Tom must perform a task. After the children are returned Tom finds an envelope left for him. It contains a syringe filled with an unkown substance and a note that reads "Kill Isabelle". At The 4400 Center, Richard discovers that Shawn and Isabelle have been engaged in a physical relationship. The Nova Group contacts The Center and offers to save Shawn's head in exchange for meeting with Richard. Richard doesn't meet with them and in response, the Nova Group finally exacts revenge on Shawn. Daniel Armand uses his ability to afflict Shawn with a mental illness.

The season opens soon after we saw Isabelle become an adult. Richard not only has to deal with this occurrence, but the discovery that his wife, has aged decades in a matter of moments. Meanwhile, Tom and Diana deal with a radical 4400 organization called the Nova Group. In a broadcast, the Nova Group promises the world a demonstration of their power on October 19. In order to expedite the investigation, NTAC brings in Gary Navarro to assist. Tom and Diana soon discover that Gary works with the Nova Group. At the 4400 Center, Isabelle tries to be an adult and Richard tries to find a way to save Lily. Meanwhile, Diana attempts to help her daughter, Maia, who has trouble controlling her visions now that she is no longer on the inhibitor. Tom and Diana catch Gary, but he refuses to give any information about October 19. Later, it's learned that Shawn has been funding the Nova Group for months, unaware of their murderous intent. To right the wrong, Shawn helps NTAC arrest his Nova Group contact but this doesn't bring NTAC any closer to figuring out October 19. Maia begins attending school at the 4400 Center. Shawn helps Isabelle deal with her mother's death. Lily dies peacefully with Richard by her side. October 19 arrives and the Nova group executes its plan, which is not an act of terror, but a positive demonstration of how the 4400 can benefit humanity.

Diana and Maia are approached by a woman claiming to be Sarah Rutledge, Maia's long lost sister, born after Maia's abduction. Sarah abducts Maia. It's learned that Sarah isn't Maia's sister but an agent from the future who has been sent back to abduct Maia, and other 4400 children, to be replaced even further into the past. As a result, Maia and the other kidnapped children will be forgotten by the present. Elsewhere, Shawn has decided to do more healing within the community. His goodwill mission ends in disaster when he's attacked but left unharmed. The NOVA Group claims responsibility, and warns Shawn that there are greater consequences ahead for his betrayal.

Tom has been plagued with bad dreams since he made his deal with the future to kill Isabelle. Shawn suffers from the mental illness inflicted upon him by Daniel Armand. Tom and Diana investigate. With no lead on Daniel Armand or a cure for Shawn, Richard commits Shawn to a mental institution. Isabelle decides to pursue Daniel Armand on her own. Matthew tries to talk her out of it. Matthew reminds Isabelle of her mission. Isabelle's feelings for Shawn are more important to her. Matthew continues to object so Isabelle kills him. She then breaks Shawn out of the mental institution. Isabelle sets out to find Daniel, leaving Tom and Diana following the trail of dead Nova members she leaves behind. Isabelle tracks down Daniel Armand and forces him to cure Shawn. Isabelle takes revenge for Shawn, and forces Armand to use his ability to give himself a mental illness. Since no one witnessed the murders, Isabelle isn't arrested. Tom knows she did it. Later, Tom confronts Isabelle and reveals that the future wants him to kill her. Isabelle offers Tom an opportunity to inject her, but Tom can't go through with it. The next morning Isabelle embarks on a new agenda that starts with her going to see Dennis Ryland.

Tom, Diana and a squad of NTAC agents race to the place where they believe Gary Navarro is hiding. When they get there, they find that Gary left just moments before. Agents from the NSA bring Alana in believe she might have ties to the Nova Group. Nina explains that Haspelcorp was contracted by the NSA to find anyone involved with the Nova Group. Alana is on their list and Ryland is leading the investigation. NTAC discovers that the call that tipped off Gary Navarro came from Heather Tobey's office at the 4400 Center. Heather comes to see Tom and reveals that Alana was the only other person who had access to her office. When Alana is released, Tom confronts her. Alana admits to placing the call. She understands that the things Gary did were wrong, but she believes he was only trying to protect the 4400. Tom feels betrayed but can't bring himself to turn Alana in. At the 4400 Center, the NSA arrest Heather for tipping off Gary. The NSA is willing to hold Heather until they find the true culprit. Alana turns herself in. Tom goes to Ryland and they strike a deal. Ryland will release Alana in exchange for Gary Navarro. Tom and Diana catch Gary. But as they make the prisoner transfer, Tom double-crosses Ryland. Tom escapes with Alana and Gary, but now they are both fugitives. In the end, Tom is forced to say goodbye to Alana as she goes on the run with Gary.

With Alana on the run and Kyle still in jail, Tom is pretty lonely until a delivery boy shows up with a basket of cookies. Tom eats a few before he is called to the scene of a suicide. At the scene, Diana reveals she was also sent a basket of cookies. Before they can discuss it any further, the detective approaches and explains the suicide victim had a new drug in her system called Blink. It has traces of Promicin in it which means the drug was manufactured by a 4400. Both Tom and Diana start hallucinating. Tom sees his father Mitch Baldwin who has been dead for years, while Diana starts to see Josh Sandler, an ex-fiancée who cheated on her before their wedding. Tom and Diana learn that the cookies they received were laced with Blink. An elderly 4400 named Naomi Bonderman comes forward and admits that her ability is responsible for Blink. Naomi reveals that blink makes you see the people in your life that you have unresolved issues with. Tom and Diana eventually discover that it was Naomi's grandson, Randy, who put Blink out on the street, but he never meant to hurt anyone, he says. He sent Tom and Diana the cookies as a thank you for saving the 4400 from the inhibitor. He felt his grandmother's ability was something that could help people. Diana breaks ups with Marco. At The 4400 Center, Isabelle decides that she and Shawn should get married. Shawn, seeing no alternative, attempts to drain the life from Isabelle while she is asleep. Isabelle wakes up and explains to Shawn that his ability won't work on her. The wedding will go forward.

A monstrous Kevin Burkoff is pursued by agents from Haspelcorp. Kevin's face and body are withered from his Promicin experiments. The agents catch Kevin and take him to a warehouse to be interrogated. Satisfied that he is telling the truth, one of the agents pulls out a gun and shoots Kevin. But Kevin is able to use his regenerative abilities to heal himself and escape. Back at NTAC, Diana's concerned because Kevin's missing. To find him, Diana is reveals to Tom and NTAC that she's been helping Kevin with his Promicin experiment. Tom and Diana go to see Tess Doerner. Tess has made a nice life for herself since she was discharged from the psychiatric hospital. She claims she has not seen Kevin. That night, Diana is in bed when she suddenly wakes up and goes to the front door. Tess is there. We learn that for some time Tess has been using her ability to bring Diana to Kevin so that he could inject her with Promicin. Kevin regrets doing this without Diana's consent, but feels it's necessary for his experiment. Tom and NTAC discover what Kevin is doing and are able to extract the Promicin from Diana's system before it's too late. Kevin and Tess escape. Kevin is able to shed his monstrous skin and come out looking like new. Richard goes to Heather Tobey for help honing his telekinetic ability. Isabelle, unbeknownst to anyone else, is revealed to be supplying Ryland and Haspelcorp with a stock pile of Promicin.

Darren says Tim could change the future, unless he's stopped. Tim's screams fill the woods. Tim's body is discovered in a way that could only be caused by a 4400 ability. Tom and Diana investigate. Darren gets a second victim. He leaves a fingerprint that matches to Darren Piersahl. Piersahl isn't a 4400. He was supposedly killed in action in Iraq in 2005. Marco discovers the Starzl Mutation, a harmless alteration to the eleventh chromosome, which all of Pierschal's victims have. When Diana and Tom get a list of people those thus affected, they find that HaspelCorp also has a copy of the list. The US government, by way of Isabelle and Ryland, have gotten hold of a supply of promicin and has started an enhanced soldiers program. Tom and Diana meet John Shaffner, the man who supposedly "died" with Darren Piersahl. He believes Piersahl is hunting down people with the Starzl mutation because if those people have a child with a 4400, the child will develop an ability. Tom and Diana confront Ryland. Ryland announces, to the public, to the world, the enhanced soldier program on television. Meanwhile, Shawn receives a gift from a 4400: a cigar that allows you to see the future when you smoke it. When Shawn puffs, he sees a vision of himself in the future, killing Richard. Later, after discussing it with Richard, he smokes the cigar again. Things are much worse. The prefereable outcome would be achieved by going through with the marriage to Isabelle. When he smokes for a third and final time, Shawn discovers the true meaning of his first vision. Thoughts of betrayal resounding in his mind, Shawn arrives at his wedding. Awaiting him there is the biggest shock of all: Jordan, alive.

Jordan asks Shawn in a bewildered manner: "Do you know who I am?" Jordan runs away before anyone can catch him. A search of the area finds nothing. Shawn insists on looking for Collier, in spite of the wedding and Isabelle. Tom goes to see Kyle in prison. He tells Kyle that Jordan is alive. Tom, Diana and Shawn soon find where Collier has been living. They find a journal. The journal talks about the future. "The war for the future will be fought in the past." Tom and Diana's investigation leads them to an encampment of homeless people. They know Jordan as "the preacher." One explains that he didn't know "the preacher" was Collier, but whoever he is the guy claims to have been to the future. Collier may not remember who he is, but he's returned with a purpose. Jordan visit's Kyle in prison. Jordan can't remember his identity. Alana is brought in to help recover Jordan's memory. The process works. After leaving NTAC the first thing Jordan does is get Kyle out of jail. Jordan confronts Isabelle. He forces her to elave the Center. April makes a with a new boyfriend, Ben. Maia that Diana is the one who is supposed to marry Ben. Diana reveals Maia's prediction to Ben and says that they have to stay away from each other for April's sake. Ben breaks up with April, leaving her distraught, and pursues Diana.

Jordan stresses that 4400s and non-4400s must work together in order to prevent a bleak future. A 4400 breaks into NTAC and helps members of the Nova group escape. Shawn learns that Jordan coordinated the jailbreak and has other plans. Shawn goes to NTAC and reveals Jordan’s plan. When they confront Jordan, he reveals it was all to test Sawn's loyalty. Jordan denies he had anything to do with the jailbreak. Richard sides with Jordan. Jordan steals HaspelCoprs stock of promicin. Shawn, Richard, Kevin Burkhoff, and Tess Doerner gather at a warehouse where the stolen promicin is being stored. Jordan wants to give it away to everybody. Meanwhile, Kyle is finding it difficult adjusting to life outside of prison. Kyle goes to see Collier. Jordan explains that his death had to happen and that Kyle is a part of a much larger plan. Kyle explains to Tom that after talking to Jordan, he has decided to leave. Tom tries to talk Kyle out of it, but his son explains that this is something he has to do.

Devon, a 4400 Center employee, has volunteered to inject herself with promicin and is filmed. Tom and Diana watch the video. Devon explains that shots of promicin will soon be available to everyone. Tom and Diana question Jordan Collier, but he claims that he had nothing to do with it. Ben tells Diana that he is going to be in Spain for six months and wants her and Maia to come with him. Devon goes into convulsions. Shawn tries to heal Devon, but to no avail. NTAC uses clues from the video to determine her location. Kevin and Tess get away, but Shawn is too overwhelmed by Devon's death to escape and he is taken back to NTAC. Jordan, Richard, Kevin, Tess, and Boyd Gelder where the stolen promicin is being stored. Richard and Jordan argue. Ryland reveals that half of the volunteers who took promicin in the super soldier program died within the 48 hours. Anyone who takes promicin has a fifty-fifty chance. Ryland shows up at NTAC with Isabelle. Ryland takes over Shawn's interrogation. Isabelle gets the information she needs but puts Shawn in a coma. Isabelle ends up at the warehouse where the promicin is being stored. It's fake. Boyd Gelder blows up the building. Isabelle survives and makes her way to the 4400 Center. Jordan hands out backpacks full of vials of promicin to a group of homeless people who have committed themselves to his cause. Isabelle enters a classroom full of children, including Maia. Isabelle is about to attack, when Diana shoots Isabelle several times. Tom attempts to inject her with the syringe the future gave him. As Isabelle strangles Tom, Richard enters and uses his ability to pick up the syringe and inject Isabelle. Although it does not kill her, she no longer has any abilities. Tom shoots Isabelle in the shoulder to make sure she can't heal herself and that her powers are really gone. Isabelle is alive, but no longer has any promicin in her system. Diana comes by Tom's house with Ben and Maia to say goodbye. Diana has decided to go to Spain with Ben. Elsewhere, Kyle gets ready to inject himself with promicin, NTAC closes the 4400 Center, Alana is abducted in a ball of light, and April Skouris stands in line to get a shot of promicin.