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Six months after the fall, Coulson's S.H.I.E.L.D. is illegal, tiny, and hunted by the government, with General Glenn Talbot on its tail. The team has new blood: Lance Hunter, the mechanic Mack, and later Bobbi Morse. Fitz survived, but he has brain damage and struggles to speak and think like before. Simmons is gone, and it soon turns out she's undercover inside Hydra. Ward is locked in the base's basement, offering intel in exchange for talking to Skye.
The big object of the season is the Obelisk, an artifact that kills whoever touches it. Hydra, led by Daniel Whitehall, wants it. So does Skye's father, an unstable doctor named Cal. The symbols Coulson kept carving turn out to be the map of an ancient city. Coulson ends up killing Whitehall, but the race for the Obelisk takes everyone to an underground Kree temple.
Inside, the Obelisk opens and releases the Terrigen Mist. Skye goes through the change and gains the power to create vibrations and quakes. Agent Trip dies in the same scene, and Raina comes out with a changed body. Skye learns she's an Inhuman, descended from humans the Kree altered thousands of years ago, and that her birth name is Daisy. Scared, she can't control the power and has to step away from the team.
The team splits. Bobbi and Mack are working for another S.H.I.E.L.D., the so-called real S.H.I.E.L.D. run by Robert Gonzales, who distrusts Coulson and people with powers. Skye goes to Afterlife, an Inhuman refuge led by Jiaying, who turns out to be her mother. Jiaying seems warm, but she's planning a war. She kills Raina, kills Gonzales, and fakes an attack by S.H.I.E.L.D. Meanwhile Ward, free again, loses his girlfriend Kara and swears revenge.
In the end, Jiaying tries to spread Terrigen crystals around the world, which would kill a lot of people. She tries to drain Skye's life, and Cal kills Jiaying to save his daughter. Coulson grabs a crystal and loses his hand, which Mack cuts off to save him. Cal gets new memories and a quiet life as a veterinarian. Coulson tasks Skye with gathering people with powers, Ward takes over what's left of Hydra, and Hunter saves a wounded Bobbi. The final scene is the hook: a Kree monolith stored at the base swallows Simmons in front of everyone.