After living for 8 years in an alternate world that only Tom and Alana remember the world with the 4400 has returned as it was at the second the 8 years started. A 30 year old 4400 woman wakes up and finds everybody else in her local community dead. Maia puts April's love for her to a test.

A 4400 with the ability to repair damaged chromosomes hides a shocking past. And while Richard seeks out a tormentor among his Korean War buddies, Shawn reconnects with his family and tries to help Kyle.

NTAC is keen to find Jordan Collier's killer as Tom is desperate to find Kyle.

A 4400 terrorist releases a signal at NTAC that makes the men violent, forcing a lockdown of the facility. Lilly questions how the Centre is handling her daughter, and Shawn tries to recruit a familiar face.

When 4400s around the world come down with life-threatening illnesses, Ryland comes back to NTAC and orders the sick - and even unaffected 4400s - to be quarantined. Tom and Diana race to find a cure and discover a shocking secret in the process.

Discovering that NTAC is behind the disease plaguing the 4400s, Tom and Diana try to get to the bottom of NTAC's cover-up, while Kyle considers turning himself in.

Ryland and other government officials are on trial for withholding vital information that they discovered about the returnees when a disturbing sound is heard the courtroom. Tom and Diana, with the help of Gary Navarro, try and track down T.J Kim, who they believe is responsible for the piercing sound heard in the courtroom. Richard and Lily are forced to deal with a now grown Isabelle While Lily also suffers from a rapid aging disease that Shawn is unable to heal. Tom and Diana also investigate a radical organisation called the Nova Group that appears to have ties with Shawn and the 4400 Center.

Gary Navarro is arrested for the second attempt to assassinate Dennis Ryland. Knowing she is the key to her mother's survival, Isabelle attempts to kill herself by jumping off the 4400 center building only to survive without a scratch. Matthew Ross expresses his displeasure at her actions and tells her of the destiny she is to face. Isabelle is troubled about what Matthew told her, but after a discussion with Shawn she decides it's her choice with what she does with her life. Matthew gives Isabelle a substance that can kill her if it's injected.

Tom is accused of murdering TJ Kim. 17 year old Boyd Gelder has the ability to change his appearance whenever he chooses. Meanwhile, Shawn and Isabelle grow closer.

Someone is targeting young 4400's and Maia gets kidnapped. A mistake from Shawn's past comes back to haunt him. Richard is given a position of authority at the 4400 Center.

Tom and Diana continue to investigate the disappearance of the 4400 children. Isabelle and Shawn's relationship becomes public.

Isabelle seeks revenge on the Nova Group after they attack Shawn. Alana confronts the man responsible for killing her husband and son in a car accident nine years ago.