Everyone on Earth is excited about a comet passing by, but as soon as its trajectory changes to a collision course, everyone starts to panic. The comet turns out to be a giant ball of light that, after exploding, leaves behind 4400 people. They are missing persons who have been gone from a few months to 60 years, and none have aged a day. The 4400 are put in quarantine and eventually released. Some of the returnees begin to exhibit strange and uncontrollable new abilities. Tom Baldwin and Diana Skouris, two Homeland Security agents, are appointed to find out what happened to the 4400.

David is a little freaked out when his ex-fiancee, Jennifer, calls to ask him to handle her father's funeral. Seeing Jennifer brings up old guilt issues for David, who still feels bad for breaking off their engagement after finally admitting that he was gay. Luckily, Jennifer is engaged to someone new, which relieves David of some guilt. However, when he tries to comfort her at the funeral, she lashes out at him, unleashing years of pent-up anger over David lying to her about his homosexuality. In the end, she is able to forgive him and the closure gives the pair a sense of peace.
In the midst of David having to re-visit his closeted past with Jennifer, Keith admits that he is still not out on his job. To David's annoyance, Keith asks him to temporarily stop answering their home phone until he's had time to switch his work contact information to his cell phone. Then, at work Keith is singled out by the young pop diva, Celeste, for peeing in her private bathroom and his fellow bodyguards enjoy a good laugh at his expense.
Inspired by her recent encounter with the fearless Edie, Claire speaks up during a class critique of her friend Anita's artwork and then takes the initiative to ask fellow classmate, Jimmy, out on a date. Claire enjoys her new-found boldness until Jimmy asks her to tell him what she likes sexually and she suddenly reverts back to her former shy self. Later, when she relates the embarrassing story to Anita and Edie, they get Claire to admit that she's never had an orgasm.
Ruth and George receive another unwanted package in the mail, this time a toy dump truck full of feces. Ruth is ready to call in the authorities to hunt down the suspected Arthur until George reveals that toy dump truck belongs to his estranged son, Kyle-a child he never told Ruth about. Meanwhile, Federico gets increasingly annoyed by Sophia's calls and demands on his time, but is still unwilling to end their relationship.
Nate's in-laws, Barb and Hoyt, invite Maya on their family trip to Lego-land for the weekend. Temporarily relieved of his parental duties, Nate is not sure what to do with himself and ends up going to see Brenda. Brenda and Joe are in the middle of role-playing sex when Nate unexpectedly knocks on the door. Despite the awkwardness of the initial moment, Brenda invites Nate in and, along with Joe, the three spend a friendly evening together.
Later, Brenda and Joe have dinner with Margaret, who is now living with Olivier, Claire's and Billy's former art teacher (and Billy's ex-lover). During dinner, Brenda mentions seeing cute pictures of baby Maya and Margaret drunkenly suggests that Brenda wants to have a baby of her own. Later that night, Joe admits that he, too, wants kids and that he's interested in having one with her.
Nate smokes pot and goes for a run. Things get weird when, from out of nowhere, a dog starts running along side of Nate. In his drugged up state, Nate sees something in the dog's eyes that makes him think of Lisa. He follows the dog to the rundown house of a psychic who tells Nate, cryptically: She isn't dead. She's trying to get back to you. Nate is shaken by the experience and briefly entertains the possibility that Lisa is still alive.

Michael, Ben, Hunter, Ted, and Justin are preparing for the Liberty Ride. Justin is surprised to find Brian has been secretly training in order to go with them. Justin supports him and is very proud and excited that they'll be riding together. However, Justin is ultimately the one who will have to bow out when Brett Keller requests that he fly to Hollywood to help him pitch Rage to the execs of the studio.