Part one
Following the events of "Scars", having killed Robert Gonzales and shot herself to provoke a war between S.H.I.E.L.D. and the Inhumans, Jiaying also secretly sends Gordon and other Inhumans to hijack nearby quinjets and fire missiles at Afterlife, making it appear that S.H.I.E.L.D. is attacking. The Inhumans declare war on S.H.I.E.L.D. and attempt to force them out of Afterlife, and Skye uses her powers to defeat Melinda May, who is rescued by Jemma Simmons. Jiaying secretly drains the life force of a captured agent to heal herself. Phil Coulson realizes that Jiaying is trying to turn the Inhumans against them, and as S.H.I.E.L.D. try to respond to the crisis, Alphonso "Mack" Mackenzie, who is preparing to leave, stays on board the Iliad to help.
Having experienced more visions of the future, Raina realizes her destiny is to ensure that Skye discovers the truth about her mother and becomes the Inhumans' new leader. After telling this to an uncomprehending Skye, Raina meets with Jiaying and threatens to stop her, prompting Jiaying to kill her. Skye witnesses this, just as Raina intended, and realizes that Jiaying killed Gonzales and orchestrated the missile strike. Jiaying reluctantly has Skye knocked out and imprisoned.
Realizing Bobbi Morse is missing, Lance Hunter reviews the CCTV and sees a duplicate May leaving with her, leading him to realize Kara Palamas and Grant Ward have kidnapped her. Ward and Palamas torture Morse to get her to admit her guilt, but she is defiant, insisting she made the right decision. Hunter and May lead troops to rescue Morse, but Ward sets up a rigged gun, so that if anyone finds Morse, they will be shot dead.
Simmons learns Cal has taken an ill-conceived and potentially fatal super-strength serum. Cal suffers a heart attack, but when Simmons administers adrenaline to save him, the completed super-soldier serum causes Cal's appearance to become more monstrous and enhances his strength, and he attacks Coulson, Leo Fitz and Simmons. Meanwhile, the Inhumans seize the Iliad, but Mack evades capture. Jiaying brings a number of Terrigen crystals aboard the vessel, intending to unleash their contents upon the entire world, to cause the Terrigenesis of every dormant Inhuman, and eradicate the human race.
Part two
Pinning Cal to a wall with a truck, Coulson tells him that he is destroying himself for Jiaying, and that she is a monster, but Cal is not. Cal admits that he believed if he could find Skye, he could make Jiaying the benevolent person she was before Daniel Whitehall mutilated her. Accepting that his wife is a danger to his daughter, Cal agrees to join forces with Coulson to stop Jiaying.
In a shootout with Hunter and May's team, Palamas impersonates May to trick them, but Ward mistakes her for the real May and kills her. Morse throws herself in front of the rigged gun when Hunter finds her, and is seriously wounded. Hunter and May bring Morse back to the Playground and Simmons operates on her to save her life, before telling Fitz that she is ready to address their feelings for each other once the crisis is over.
Aboard the Iliad, Mack rescues Skye from the other Inhumans. Discovering an SOS has been sent out, Jiaying kills Oliver and several other agents with a Terrigen crystal to coerce Weaver into expanding the beacon, so that all of S.H.I.E.L.D. will come to the Iliad and be massacred by her vast Terrigen supply. Skye convinces Lincoln to help her stop Jiaying and hacks the SOS to warn Coulson of Jiaying's trap, and after warning the rest of S.H.I.E.L.D. to retreat, Coulson, May, Fitz and Cal board the Iliad. Jiaying sends Gordon to release Terrigen mists into the Iliad's ventilation, to kill all humans on board, but Mack, Coulson and Fitz fight to stop him. Fitz uses devices to contain Gordon's teleportation to the fan room, and Gordon accidentally impales himself on a piece of rebar and drops a crystal, which Coulson catches to stop it from releasing the tainted Terrigen. The crystal petrifies his left hand, but Mack severs it with an axe to save his life. Jiaying has other Terrigen crystals loaded on a quinjet to spread the mists across Earth, and tries to drain Skye's life force when she tries to stop her. Skye knocks the quinjet into the ocean with her powers, before Cal kills Jiaying.
Mack rejoins S.H.I.E.L.D. and is put in charge of all alien artifacts by Coulson, while Morse withdraws from field duty to recover from her injuries, and May takes a leave of absence to try to resume her relationship with Andrew Garner. Cal's memories are erased, and he is given a new identity as a vet named Winslow. Skye visits him after his practice opens, without revealing herself as his daughter, and begins going by her birth name, Daisy Johnson. Coulson decides to try and give the Inhumans a new purpose by forming a new S.H.I.E.L.D. team, and appoints Daisy as their leader, under Mack's supervision, and with Andrew analyzing potential candidates. As yet unbeknownst to them, the submerged quinjet has introduced Terrigen into the ecosystem, with fish drinking it resulting in tainted fish oil. Meanwhile, an embittered Ward, blaming S.H.I.E.L.D. for Palamas' death, takes command of what is left of Hydra, since Dr. List and Wolfgang von Strucker were killed in the events of Avengers: Age of Ultron.
In an end tag Fitz finally arranges a date with Simmons, but after he leaves the room, the Monolith breaks free of containment and absorbs Simmons into itself.