As the team deals with the loss of Trip, Skye remains in quarantine to make sure that whatever infected Mack hasn't spread to her as well. Meanwhile, the heads of HYDRA discuss what to do now that Whitehall is dead.
After surviving events on the Helicarrier, S.H.I.E.L.D. Agent Phil Coulson puts together a small team of S.H.I.E.L.D. agents to handle strange new cases. They investigate Project Centipede, eventually uncovering that Centipede is backed by the organization Hydra, which has infiltrated S.H.I.E.L.D.
Following the destruction of S.H.I.E.L.D., Coulson and his team look to restore trust from the government and public while dealing with Hydra and the newly revealed Inhumans, people who possess special abilities. Coulson's work is further complicated by the appearance of another faction of S.H.I.E.L.D. agents who do not trust his leadership.
Coulson begins a secret mission to assemble a team of Inhumans to deal with new threats to the world, while Hydra returns its ancient banished Inhuman leader to Earth.