A man is killed in a fire in his home, but his girlfriend escapes. Meanwhile, Horatio must fire Ryan when he doesn't disclose that he knew one of the suspects.

Horatio hunts for a serial killer who brands his victims with a "Y" mark. When an arrest is made, the alleged culprit is found to possess a supposed "killer gene" due to an extra Y chromosome. But just as the CSIs believe they've closed the case, the killings begin again.