Through an online video, Devon reveals to the world that she is going to start injecting herself with Promicin and that it will be available to the public soon. However, her body later rejects the Promicin, and Shawn is captured by NTAC while he tries to heal her. He refuses to tell where the Promicin is being held, but Isabelle manages to get the information from him. Predicting that she would find the location, Collier takes the Promicin from the warehouse and plants a bomb. However, Isabelle survives and decides that the only way to draw out Collier is to attack the 4400 Center.
The 4400 tells the stories of 4,400 people who disappeared over a period of fifty years and who all reappear at the exact same time without any memory of where they've been and what happened to them. Some of them have been altered and have strange abilities, both good and bad.
The series kicks off with a ball of light sailing toward Earth, but rather than the expected catastrophic event, thousands of people emerge from the ball of light. The returnees have been missing from a few years to several decades and no one has aged a day.