Season One
Over the past sixty years, 4400 people have gone missing, some are presumed dead. The reason? A mysterious ball of light from the future was a mission to retrieve people from throughout the timeline. In the year 2004, the ball of light returns, and it has a special delivery: 4400 people.
Homeland Security is quick to the scene to watch as the ball of light explodes and deposits 4400 people on the beach. They are rounded up and put into quarantine. It soon becomes apparent to that these people have returned with new abilities. Abilities that cannot be explained in the present. Homeland Security creates a special division, known as NTAC (National Threat Assessment Command) to follow The 4400. Tom Baldwin and Diana Skouris, a crime investigator, and bio medic, are teamed up to investigate The 4400.
New cases continue to pop up that involve members of The 4400. Each case opens more questions. Who took them? Who sent them back? Why now? They learn that it was Humans from the future that took these people, changed them, and then sent them back. They were sent back to the year 2004 because it was determined that was 'where the path to oblivion began'. These 4400 people will play a pivotal role in events that will impact the very future of mankind.
Season Two
It has been one year since the events on Highland Beach revealed that humans from the future are responsible for taking and returning these people. After extensive medical examinations, Tom Balwdin returns to NTAC in a limited role in the form of desk duty and secures the release of his son from quarantine. Diana Skouris, finally manages to get Tom away from his desk job and back on the field, where he is at his best. Diana formally adopts Maia as her daughter amid all that has happened.
Richard, Lily, and their baby daughter Isabelle, are still on the run from Jordan Collier. Collier, who is obsessed with finding them, has closed his Arcadia Estates and opened "The 4400 Center", where normal people attempt to 'bring the 4400 out of them'. After healing Jordan from the effects he received from having touched Lily's womb, Shawn has formed a strong bond with Jordan. The world has changed, and many are curious about The 4400. Rumors are started about their abilities and soon the public is divided between those who fear them and those who embrace them.
A government conspiracy is soon uncovered. NTAC was giving promicin inhibitor to The 4400. This was done to block The 4400 from being able to use their powers. But it turns deadly as the inhibitor begins to turn into an infection that is only affecting The 4400. Those with powers lose their ability to use them. Kevin Burckoff, who was suffering from a mental illness and was 'awakened' by a 4400, discovers an antidote, but needs a 4400 that wasn't infected with the inhibitor. Isabelle willing lets tests be done so The 4400 can be cured. Upon creating only one vile of the cure, Diana takes the job of getting into quarantine and to inject it into Shawn. Upon receiving the injection, Shawn regains his healing power and begins to heal the other 4400. In the aftermath of this, several government officials are arrested for taking part in this plot.