Daisy has left S.H.I.E.L.D. and is trying to solve the mystery of a bunch of serial killings in the Los Angeles area. At the same time her old friends suspect her for the killings and are following her trail in an attempt to find her.
Coulson, Mack and Fitz try to locate and neutralize a rogue group looking to stop Inhuman registration worldwide; Simmons and Dr. Radcliffe have only a short time to save May before she succumbs to her illness.
As Ghost Rider's quest for vengeance brings him into an explosive confrontation with S.H.I.E.L.D., Coulson and Mack must rely on an unlikely ally in their time of desperate need; and Daisy reunites with a familiar face to stop the Watchdogs.