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A comet is due to pass by Earth, but its trajectory changes to a collision course, causing widespread panic. When the comet appears to slow down — as if it's coming in for a landing — 4,400 people are deposited in explosion over Highland Beach.

The returnees — "the 4400" — have been missing from months to years. None have any memory of where they've been, none have aged, and a small number are beginning to manifest paranormal abilities. Tom Baldwin and Diana Skouris, two Homeland Security agents, are appointed to find out what happened to the 4400.

Carl Morrissey is a lowly supermarket employee who happens to be one of the 4400. He uses his new found powers - enhanced reflexes and strength - to become a vigilante and fight crime in his neighbourhood. Lily is thrown in jail for violating the restraining order while looking in on her daughter and ex-husband's new life. Richard and Lily's romance begins to blossom.

Tom and Diana are sent out to investigate a homicide that resembles the MO of a serial killer who was never caught nor heard of for 21 years. The first suspect is Oliver Knox, a member of the 4400. However, Knox has an alibi for the night of the murder and another man confesses to the crimes. Tom and Diana suspect that Knox is luring people to kill for him and try to lay a trap on him. Meanwhile, people begin to turn hostile towards the 4400, and Jordan Collier decides to organize his fellow returnees. But Richard feels uneasy about Collier's interest in them.

The 4400 are attacked by a series of bombings after Barbara Yates makes their names and addresses known to the public. Tom, Diana and Dennis try to put an end to the bombings, while at the same time Tom is coping with Kyle's erratic behaviour.

Warren Lytell, an agent from Washington is sent to "monitor" the teams progress on the 4400 investigations. Jordan Collier offers protection to members of the 4400, while Richard and Lily begin to question his motives.