Tom and Diana investigate a mysterious structure being built at a psychiatric hospital, based on the drawings of one of their patients who's a 4400.

Richard must protect his family when he and Lily are discovered to be 4400s.

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.

Kevin is on the run after horribly mutating due to the promicin experiments. Tom and Diana go to Tess for help. Diana gets what she believes is the flu and discovers something startling.

NOVA group members that were in the custody of NTAC escape from jail with outside help from Jordan Collier. Diana tells April about her relationship with Ben. Shawn and Richard learn that Isabelle is working with Dennis Ryland.

Tom and Diana continue their investigation on Jordan Collier's plan for mankind. Dennis Ryland rejoins NTAC. Isabelle prepares for battle.

A high school student develops an ability after injecting promicin. Tom visits Isabelle in jail, while Diana searches for her missing sister. Following the advice of a young woman, named Cassie, Kyle is able to wake Shawn from his coma. Jordan Collier's conscience gets to him. Meanwhile, NTAC gets a new director.

Richard surprises Isabelle when he shows up in Promise City but the happy reunion takes a turn when Richard kidnaps her in hopes to start a new life with his daughter.

Tom has trouble focusing on the hunt for Richard Tyler because of dreams he's having about the future.

Tom and Diana must race to find the source of a computer virus that could bring down Ubient software, one of the world's largest software companies that is run by suspected member of the marked, Drew Imroth. Meanwhile, Maia visits Promise City where she receives an unexpected birthday surprise: a visit from her birth parents.

Meghan and Diana learn how to remove the entity from Tom, but the procedure is dangerous.

Meanwhile, Shawn finds help in his attempt to rescue Kevin from Promise City; and Jordan is betrayed by someone close.

Paramedics try to resuscitate Susan Farrell. They believe that she took promicin and lost the 50/50 lotto that comes with it. Danny is certain that she did not take the shot. After arriving at the hospital with the paramedics, things get complicated as everyone around Danny start to die. Garrity and another NTAC agent are sent to the hospital to assess the situation.