Mulder is less than thrilled when an Office of Professional Conduct board refuses to reassign him and Scully to The X-Files and even more so when he learns that Agent Spender and Agent Fowley have become their successors. When Gibson Praise reappears and comes to them for help, Mulder and Scully attempt to continue their quest undercover despite having fewer friends and less access and protection than ever before.

Mulder and Scully have 24 hours to save A.D. Skinner from being killed by a biologically engineered disease. The disease appears to be created by a shadowy government organization, but in order to save Skinner's life they must determine who wants him dead and why. With Skinner's condition worsening, Mulder seeks assistance from Senator Matheson, who he hopes can provide some answers and help him to find a cure.

While the Cigarette-Smoking Man recites to an unseen listener everything about the work of the Syndicate involving a global conspiracy in cooperation with an alien species, Cassandra Spender reappears and is pursued by the scientists who would rather kill her than keep her alive. Cassandra runs to Mulder's apartment and demands that he shoot her because she is the culmination of 50 years work - a living alien/human hybrid - and colonization will begin if the aliens find out about her.

The Cigarette-Smoking Man reveals all the government secrets from the past 50 years in order for his son, Jeffery Spender, to join him in his work. Mulder learns that the final stage of the conspiracy will soon begin with the hybridization of the Syndicate members, and he must stop it from happening. Agent Spender deceives his father and arranges for Mulder and Scully to be reassigned to the X-Files, which doesn't sit too well with the Cigarette-Smoking Man.

Two scientists confer about each of their metal objects that were found in Africa and they theorize that the objects are pieces of a puzzle which could be undeniable proof that human, plant, and animal life did not originate on this planet. When one of the scientists is killed and the objects are stolen, the agents investigate and Mulder begins to experience severe neurological pain caused by the objects.