In Nina's absence, Dennis Ryland oversees Tom and Diana's investigation of a deadly epidemic affecting the 4400. Meanwhile, Isabelle is examined without Lily's consent; Alana begins confusing reality with the fantasy she shared with Tom; and an ailing Shawn abdicates control of the 4400 Center.

Tom and Diana discover that the source of the disease that threatens the lives of the 4400 is linked to a conspiracy to inhibit their burgeoning abilities. Meanwhile, Lily experiences harrowing hallucinations; Richard organizes resistance to the quarantine; and Kyle decides to own up to the Collier shooting.

Richard is forced to cope with his infant daughter's sudden transformation into a woman and a horrendous change in his wife, Lily. Meanwhile, Dennis Ryland is injured during Congressional hearings, and the person responsible may be part of a radical 4400 splinter group.