Premise: A new beginning is underway for the 4400 people who, over a span of years, mysteriously disappeared - only to be returned to Earth all together in a ball of light. Though the returnees had not aged physically, many of them reappeared with dramatic abilities ranging from enhanced reflexes to precognition. NTAC (National Threat Assessment Command) is the government agency responsible for keeping track of the returnees and investigating all things related to the 4400.

The third season picks up mere seconds after we last saw a year-old baby, Isabelle, become a beautiful twenty-year old woman. Her father, Richard, is forced to deal with his daughter's sudden transformation -- and an even more surprising change in his wife, Lily. Meanwhile, Tom and Diana pursue a radical 4400 organization called the Nova Group that has launched attacks against Dennis Ryland and the other bureaucrats involved with the inhibitor scandal. At the 4400 Center, Shawn is forced to contend with the new Nova threat and the interests of Isabelle.