The National Threat Assessment Command (NTAC), a division of the Department of Homeland Security, is in charge of dealing with the return of the 4400. The primary agents assigned to the cases of investigating the 4400 are Tom Baldwin and Diana Skouris, as well as their immediate superior for season one, Dennis Ryland. In seasons 2-3, Ryland is replaced by Nina Jarvis and theory room consultant Marco Pacella with Ryland becoming a recurring character. Season 4 sees Jarvis replaced by Meghan Doyle.

Many of the returned people have trouble trying to get their lives back on track after being separated from their world for years. More significantly, a small number of the returnees begin to manifest paranormal abilities, such as telekinesis, telepathy and precognition, as well as other "gifts". For example, in the pilot episode Shawn Farrell manifests an ability to bring a dead bird back to life. In addition, one of the 4400 (Lily Moore) has become pregnant between her disappearance and return.

The first season finale, "White Light", reveals that the 4400 were abducted, not by aliens, but by humans from the Earth's future; that Kyle Baldwin was to be their "messenger"' and that they were returned to avert a catastrophe.

By the second season, it is revealed that all 4400 have a neurotransmitter called promicin in their brains, which gives them their powers. The government, afraid of what this large group would do with such power, secretly doses all 4400 with a promicin-inhibitor which works on most of the 4400, but not those who were later seen with powers. The inhibitor causes a potentially fatal immune deficiency as a side effect in the returnees. It is ultimately removed from the 4400 by a dose of promicin extracted by Kevin Burkhoff from the blood of the infant Isabelle, who was never given the inhibitor.

At the beginning of the third season, the Nova Group, a terrorist faction made up of 4400s, has made itself known. Originally formed as a "defensive" group in the aftermath of the promicin-inhibitor scandal, the Nova Group eventually carries out numerous terrorist attacks against the government and NTAC. The group is responsible for many terrorist attacks including the assassination of the men involved with the promicin-inhibitor conspiracy; the attempted assassination of Ryland; the framing of Baldwin for murder; and the driving of another person to insanity.

During the third and fourth season, it is revealed that only a certain faction from the future wants to see history changed. Another faction, that prefers the status quo, opposes the 4400, and has sent their own operatives, including Isabelle Tyler and "the Marked", into the past. The exact motives of both factions have not yet been revealed.

Eventually, Jordan Collier, who declares himself the savior of humanity, makes promicin shots available to the general public. However, only half of the human population can actually tolerate promicin, and thus develop superhuman abilities, while the other half die upon taking the shot. Although the government outlaws promicin use, thousands of previously ordinary people have developed superhuman abilities, severely complicating NTAC's task. Collier later annexed a part of Seattle and transformed it into "Promise City", a self-proclaimed paradise open to all people with superhuman abilities. Attempts to reclaim Promise City by the US government have met with little success, and considering the damage certain 4400s loyal to Collier could do, NTAC has advised caution in attempting to do so by force.