Forty-four hundred people who have gone missing over the last 60 years suddenly appear at the foot of Mt. Rainier, Washington. Soon, it becomes evident that some of them have been changed, gifted with special abilities. It's up to NTAC agents Tom Baldwin and Diana Skouris to find who took them, where they went . . . and why they have been returned.
Tom and Diana investigate a young 4400 in quarantine, Maia Rutledge, who has made comments about the future to several NTAC personnel which have come true. Also, another 4400 discovers he has been changed and decides to use his ability to improve his neighborhood. Diana takes Maia home with her.
A 4400 is a suspected of a serial murder investigation that has started up again. He is let off when his alibi comes through and another man claims responsibility. When yet another murder occurs and a second man claims responsibility as well, things get more interesting. Jordan Collier starts to gather the 4400 together behind him and Shawn Farrell wakes Kyle Baldwin from his coma with his ability. Barbara Yates is told to back off from the 4400. A list of the 4400's names and address is leaked to the net.
Several 4400s are attacked, using home-made explosives, prompted by the leaked list. Richard and Lily Tyler are offered a home in Jordan Collier's housing compound, as well as a job for Richard. Warren Lytell comes to Seattle NTAC under the guise of offering help the division, hoping to secure a higher position for himself. Shawn sleeps with his brother'sgirlfriend. Kyle has a disturbing comment for his parents.
Lytell takes Kyle out of the hospital from his parents, causing Tom to go to extremes to get him back. Jordan withholds information about Lily's child and tries to break her and Richard apart, causing the two of them to go into hiding. Shawn runs away from his family, going to Jordan's compound. The mystery of who had taken the 4400 and why is finally answered.