The second season of this intriguing series begins one year after the first. Field agent Tom has been put on hiatus, his son is still being kept in quarantine. Agent Skouras has adopted Maia, the girl from the 1940's. Richard Tyler and Lily are on the run, wanting to protect their infant daughter, Isabelle, from Jordan Collier, who wants to get his hands on her. When a group of religious fanatics track them down at their secluded cabin, Isabelle kills them with her mind. This makes Richard nervous, since his daughter only communicates with her mother. Shawn, who can heal any disease with his hands, is now working at the new 4400 Center and hasn't had contact with his family in nearly a year.
In one episode, a former baseball player exhibits mind-reading abilities, in another a salesman's (Robert Picardo) saliva causes rapid weight loss, like in THINNER. There's also a woman (Sherylnn Fenn of TWIN PEAKS) who spreads a fatal disease when she gets upset. She comes to believe that it's her destiny to wipe out mankind. There's also a 4400 who can repair bad chromosomes in the womb. It turns out he's a war criminal from Africa who is trying to make up for past mistakes. In one of the more interesting stories, patients at a mental institution start building an odd contraption, which is a device that awakens the mind of one of the patients, who may be the father of the 4400 technology. Meanwhile, Shawn becomes interested in a red-headed homeless girl, who he tries to help. Tom is put into an alternate reality, generated by a woman named Alana, where he lives out the next twenty years. When he awakens he finds that their experiences--and love--is real, and continues a relationship with her. The people from the future, who had abducted the 4400 to begin with, tell Tom that he'll need Alan's emotional support because of what is to come. This turns out to be the assassination of Jordon Collier (Billy Campbell) by Tom's son, Kyle, who was obviously being controlled by someone else's mind. Kyle feels guilty and ultimately turns himself in because he doesn't want an innocent man being found guilty for his crime. However, soon after he was shot, Collier's body vanishes into thin air. It's not until the very last episode that we see that he's still alive, on the other side of the world. Meanwhile, Shawn is left to run the 4400 center with the help of one of Collier's associates who is not what he appears to be.
The authorities, led by Dennis Hyland, wants to quarantine all 4400 once they begin becoming sick. But they are sick because the government has secretly been giving them injections to prevent the advent of their special "4400 abilities". Tom and Diana uncover all of this, though nearly thirty 4400's die because of the fiasco. This will set up a rift between the normal humans, the government, and the 4400's. Also, Richard and Lily stop running, but in the last episode Lily is rapidly ages--and Isabelle miraculously grows to adult-hood. She will cause a lot of trouble in Season 3....