Inhumans had bad experiences with Humans. Jiaying was dissected by Daniel Whitehall and left for dead. Eva Belyakov was killed in Manama, Bahrain by Melinda May. Coincidentally, both incidents involved the organization S.H.I.E.L.D., causing some, like Calvin Zabo, to view the organization with hostility.
S.H.I.E.L.D. has a concept called the Index where it categorizes and tracks individuals with unusual powers or attributes. Depending on the severity of the powers and personality of the person, individuals, like David Angar or Wendell Levi, could be indefinitely imprisoned or restricted in certain interactions with the public.
Since Inhumans gained their powers only through exposure to Terrigen Crystals and Terrigen Mist, Jiaying commissioned her scientists to make artificial Crystals because there were only five Diviners in her possession.
S.H.I.E.L.D. discovered the existence of Inhumans through interaction with the Kree Vin-Tak, the study of Lincoln Campbell, and the infiltration of Raina and Gordon into the Iliad. Skye, an Inhuman S.H.I.E.L.D. agent, attempted to explain to her superiors that the Inhumans were isolationist and fearful of humanity, but S.H.I.E.L.D. insisted upon meeting them as a whole.
- "Skye's mother orchestrated the whole thing. It was a performance. The Quinjet they stole only fired on the one building. Nobody got hurt."
"Except Commander Gonzales. It either killed him or destroyed any evidence of foul play against him."
"If it's theater, it worked. Every Inhuman up there believes that S.H.I.E.L.D. attacked their leader and declared war."
- ―Phil Coulson, Jemma Simmons, and Melinda May[src]
Skye and Lincoln Campbell returned to Afterlife so Skye could speak to Jiaying. Once there, Skye informed Jiaying that Phil Coulson wanted to speak with her. Jiaying reluctantly agreed and decided to use Calvin Zabo as an early peace offering. However, unbeknownst to her, Robert Gonzales was chosen to go to Afterlife instead of Coulson.
At Afterlife, Gonzales attempted to negotiate with Jiaying, first comparing her scars to his injury. He brought a necklace that Jiaying recognized as her own as a peace offering. When Gonzales revealed he wanted to put all Inhumans on the Index, a disgusted and angry Jiaying brought out her own gift: a synthetic Terrigen Crystal. Explaining how the synthetic crystals were deadly to humans, she broke the crystal, releasing the Terrigen Mist and petrifying Gonzales. Jiaying then took Gonzales' gun and shot herself twice in the shoulder, knowing her people would follow her into war.
Jiaying staggered out of the building and collapsed on the ground outside, accusing S.H.I.E.L.D. of starting a war. She asked Gordon to go after S.H.I.E.L.D., and he complied, hijacking a Quinjet and firing on the negotiation building, covering Jiaying's tracks while making it seem as if S.H.I.E.L.D. had fired on Afterlife. All Inhumans needing protection were evacuated, while the others readied for war. The S.H.I.E.L.D. agents returned to the Playground.
A team of Inhumans including Gordon, Lincoln Campbell, and Alisha Whitley teleported onto the Iliad with other teams in position to attack the ship. They quickly took over the cargo room, and soon the entire ship, with the ship's crew their hostages. Jiaying arrived with cases of synthetic crystals, and Campbell warned her that an emergency beacon had been sent out to S.H.I.E.L.D. Jiaying then ordered Anne Weaver and Oliver to expand the beacon and bring S.H.I.E.L.D. to them.
Skye, who had confronted Jiaying over her plan, was imprisoned on the Iliad but escaped with the help of Alphonso Mackenzie. She reset the beacon to warn S.H.I.E.L.D. of the danger that awaited them while Mackenzie left to guard the synthetic crystals.
Back at S.H.I.E.L.D., Coulson received the emergency signal and took agents and Quinjets to help. However, on their way, Skye's message was received, and Coulson ordered all other Quinjets to fall back, while his, with Leo Fitz and Calvin Zabo, continued. When they arrived at the ship, Coulson and Fitz left to help Mackenzie while Zabo tried to confront Jiaying, only to fail and be locked up.
Gordon arrived to remove the Terrigen Crystals, only to find Alphonso Mackenzie waiting for him there, armed with an axe. The two fought until Phil Coulson and Leo Fitz arrived, with Fitz using a device to trap Gordon inside the room. The four continued to fight until Gordon teleported onto a pole Fitz was holding, accidentally impaling himself. As he fell to the ground dying, he dropped a crystal, but Coulson managed to dive to save it from breaking. The crystal began to petrify him, but Mackenzie chopped off Coulson's arm, stopping the petrification.
Jiaying went to the deck of the Iliad, only to be confronted again by Skye. She ordered her men to begin loading Terrigen crystals onto a Quinjet while she again tried to convince Skye that S.H.I.E.L.D. was a threat and needed to be exterminated. When Skye would not be swayed, Jiaying began to kill her, sucking out her life-force. However, Skye used her own powers to create a shock wave that blasted the Quinjet, with the crystals inside, into the ocean. Jiaying, with her plan destroyed, tried to kill Skye again, only to have Skye use her powers as well. They were stopped by Calvin Zabo, who broke the two women apart and broke Jiaying's spine, killing her. 
Calvin Zabo, who had finally gained a sense of connection and bond between his daughter, Daisy, was put through Project T.A.H.I.T.I. at Skye's request so that he could have a second chance at life. In his new identity as Doctor Winslow, he opened a veterinary practice. He was visited at his new office by a young woman who introduced herself as Daisy. Noting it was a nice name, Winslow continued with his new life.
Alphonso Mackenzie later decided to rejoin S.H.I.E.L.D. and accepted Phil Coulson as the Director, who made him the head of the Alien Artifacts Department. With the Monolith moved from the Iliad to the Playground for study, he firmly stated that its container would not be opened, to the disappointment of Anne Weaver and Jemma Simmons. Later, however, Leo Fitz accidentally loosened the container's bolts while asking Simmons out on a date. When she noticed it, Simmons tried to refasten it, only to be engulfed by the stone, which afterwards retreated back into its container, leaving no trace of Simmons.
The Terrigen Crystals that were pushed into the ocean released the Mist inside. Fish absorbed the Mist and were caught in nets, used to make fish oil pills sold in stores around the world. Though S.H.I.E.L.D. was able to collect the pills, the organization could not get the ones bought before they discovered the contamination. New Inhumans emerged, including Joey Gutierrez.
The property of Jiaying was recovered by S.H.I.E.L.D., including a genealogy ledger that she booby-trapped with Terrigen Mist; the book was opened by Andrew Garner and he became the monstrous Inhuman killer nicknamed Lash.
With the rapid rise of Inhumans emerging on the planet, the Inhumans living in Attilan on the Moon notice this and Black Bolt decided to send Triton to Earth and bring these new Inhumans to Attilan.
- Agents of S.H.I.E.L.D.: 2.12: Who You Really Are
- Agents of S.H.I.E.L.D.: 2.08: The Things We Bury
- Agents of S.H.I.E.L.D.: 2.17: Melinda
- Agents of S.H.I.E.L.D.: 2.13: One of Us
- Agents of S.H.I.E.L.D.: 2.16: Afterlife
- Agents of S.H.I.E.L.D.: 2.20: Scars
- Agents of S.H.I.E.L.D.: 2.18: The Frenemy of My Enemy
- Agents of S.H.I.E.L.D.: 2.21: S.O.S. Part One
- Agents of S.H.I.E.L.D.: 2.22: S.O.S. Part Two
- Agents of S.H.I.E.L.D.: 3.01: Laws of Nature
- Agents of S.H.I.E.L.D.: 3.07: Chaos Theory
- Inhumans: 1.01: Behold...The Inhumans!