At an urban park, several male hustlers regard a potential client: Darren Piersahl. But he only has his eyes on a young man named Tim. When the two arrive at a secluded spot in the woods, Darren says Tim could change the future, change everything... unless he's stopped. Darren reaches out, and Tim's screams fill the woods.
Tim's desiccated body is discovered the next day, oxidized in a way that could only be caused by a 4400 ability. Tom and Diana are brought in to investigate the case, just as Piersahl gets his second victim. This time, they're able to nab a partial print that matches to Darren Piersahl. Problem is: Piersahl isn't a 4400, in fact, he's not even supposed to be alive. He was killed in action in Iraq in 2005.
At the same time, Marco discovers the thing tying Piersahl's victims together: the Starzl Mutation. They are all children of individuals who were exposed to a flawed radiation machine at Seattle Presbyterian Hospital. The machine caused a heritable but harmless alteration to the eleventh chromosome. When Diana and Tom go to the hospital to get the list of people affected by the Starzl Mutation, they find that someone has already beaten them to the punch: a representative from HaspelCorp, Dennis Ryland's new employer.
Marco's research and their meeting with Ryland reveal a terrible possibility: the US government has gotten hold of a supply of promicin and is using it to create enhanced soldiers with 4400 abilities. Tom and Diana get a major break when John Shaffner, the man who supposedly "died" alongside Darren Piersahl in Iraq, comes to them. He explains that he and Darren were among the first men recruited for HaspelCorp's enhanced soldier program. He believes that 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 armed with this information, they finally have a reason why the future sent the 4400 back to Seattle: so that they can procreate with people affected by the Starzl mutation and have children with abilities of their own.
With Shaffner's help, Tom and Diana track Piersahl to an old hide-out in the woods. At this point, Piersahl is so far gone that he kills Shaffner and attacks Tom. Tom is able to finish him off in a fight to the death, but at the end they're left with no one who can corroborate their evidence about Haspelcorp's enhanced soldier program. When they arrive back at NTAC, they discover they wouldn't have needed it anyway. Ryland is already announcing the program on live television, touting the soldiers as America's new heroes.
Meanwhile, Shawn receives a very special gift from a 4400 wedding guest: 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. After the wedding lunch, the two men discuss Shawn's dream and he commits to change his present course to avoid that outcome. He leaves Isabelle and the Center, his whole life, behind.
Later, desperate to know his sacrifice has made for a better future, he smokes the cigar again. But this time, things are much worse. The catastrophe has come, and Shawn must watch helplessly as his uncle, Tom, dies in his arms. Afterward, Shawn speaks with Richard, who pushes him to go through with the marriage to Isabelle. After all, his is only one life. In the second vision, thousands would die.
When he smokes for a third and final time, Shawn discovers the true meaning of his first vision: he killed Richard because Richard had started a war, using the 4400 as his personal super-powered army. Thoughts of betrayal resounding in his mind, Shawn arrives at his wedding. Awaiting him there is the biggest shock of all: Jordan Collier. Alive.