Scully helps Mulder fake his own death in order for him to go undetected through the Department of Defence and find out the answers to his new questions about the government hoax concerning the existence of extraterrestrial life. Meanwhile, at a joint FBI/DOD inquiry, Scully's attempt to drive out the Conspiracy's informant is halted as her cancer takes a bad turn.

The Cigarette-Smoking Man helps Mulder to obtain Scully's cure and also lets him see his real sister who doesn't turn out to be as happy to see Mulder as he would've liked. In return for this, the Cigarette-Smoking Man asks that Mulder quit the FBI and work for him in the Syndicate where he could have power and respect which Mulder turns down, deciding to stay on the side of justice. While Scully's cure appears to have worked, the Cigarette-Smoking Man faces his own enemies and disappears, presumed dead.

On her Christmas vacation with her brother's family, Scully receives a mysterious phone call from a familiar voice who says, "She needs your help. Go to her." The phone call leads Scully to a murder case where the victim's 3-year-old adopted daughter bears an uncanny likeness to her sister, Melissa, at that age. The emotional roller coaster that follows has Scully believing that her sister had a baby during a period when she traveled the country and she tries to adopt the child, knowing that caring for the little girl would change her life.

DNA testing on Emily reveals that she is actually Scully's daughter and Mulder comes to assist her. While Mulder is looking for any information about where and how the girl was born, Scully searches for a cure to Emily's strange illness.

Mulder and Scully meet Cassandra Spender, a woman who claims to be a multiple abductee and wants to deliver a positive message about the aliens. Mulder's new found disbelief in extraterrestrial activity is enhanced while Scully forms a special bond with the woman. A series of group attacks against abductees take place and the shadowy Syndicate believes that a rebel alien resistance is attempting to destroy all their work.

After the gathering at the abduction site where everyone is killed by the rebel bounty hunters, Cassandra Spender disappears and Mulder is blamed by her son, Jeffrey, who is an up-and-coming FBI agent. Meanwhile, the Syndicate is continuing their tests to create a vaccine for the Black Cancer and Marita Covarrubias becomes an unwilling test subject.

The Cigarette-Smoking Man returns as Mulder investigates the attempted assassination of a young boy with psychic powers who may be the proof that he has looked for all his life.