Having rebuilt its public face following the Sokovia Accords S.H.I.E.L.D. is faced with a new threat in the form of the Ghost Rider, a killer on a personal vendetta. While Mack and Coulson pursue a lead on Daisy, Fitz discovers Holden Radcliffe's side project -- and May questions where Simmons' loyalties now lie.
Daisy tracks down Robbie Reyes -- a.k.a. Ghost Rider -- and decides to confront him about his actions directly. Agents Coulson and May meet the new S.H.I.E.L.D. Director face-to-face, and a group of ghosts plan their own revenge after they realize what has happened to them.
Coulson, Fitz, and Mack track a rogue group that wants to give Inhumans a bad name, forcing the new Director to take S.H.I.E.L.D. public sooner than planned. Simmons and Dr. Radcliffe desperately search for a way to save May's life.
Daisy appeals to Simmons for help tracking down Inhumans being targeted by the Watchdogs, while Coulson and Mack get a rare opportunity to chase down Ghost Rider. Radcliffe decides to test his new project by putting her in charge of Agent May's recovery care.
Their search for the Darkhold book leads May and Coulson to a high-security prison, where they are trapped and in need of rescue after the ghost psychosis comes over the warden. Jemma worries about her ability to keep Dr. Radcliffe's secret when she must pass a high-tech lie detector for S.H.I.E.L.D.
After Daisy reunites Gabe with his brother she learns the truth about how Robbie became Ghost Rider, while they hide from Director Mace -- who is on a warpath looking to bring a killer to justice.
May and Mack try to decide what to do next following Eli's actions and the loss of half their team -- while Coulson, Fitz, and Robbie find themselves trapped in between dimensions. Elsewhere, Agents Simmons is called in to consult on a mysterious figure who has been inside a Terragenesis cocoon for months.
S.H.I.E.L.D. rallies its biggest assets in the hunt for Eli Morrow, who is building a powerful weapon that threatens all of Los Angeles. While Robbie confronts his uncle directly, Director Mace decides what to do with Dr. Radcliffe's newest invention.
Director Mace and Daisy team up to look for a newly-emerged Inhuman, who they now know to be Senator Nadeer's brother. Radcliffe and Fitz are ordered to erase any memory of the Darkhold from Aida, but get more than they bargained for when they confront her.
After an attempt on Director Mace's life Coulson, Mack, and Mace find themselves on the run from the people trying to kill him -- leading to a shocking secret about their boss. Fitz and Simmons have a disagreement over whether to study Aida.
Agent May struggles to free herself from captivity but must get past Aida, who is struggling to see much value in May's life. Daisy is summoned to answer for her actions while "undercover," putting S.H.I.E.L.D. in the cross-hairs of Senator Nadeer. Meanwhile, Mack's personal life threatens to come between him and Elena.
After Agent Billy Koenig is captured by the enemy in search of the Darkhold, his brother and the rest of S.H.I.E.L.D. turn to another member of the family to try and rescue him. Meanwhile Fitz attempts to probe his new L.M.D. prisoner, and May draws closer to fulfilling her secret mission.
Coulson tracks down the woman who served as Radcliffe's model for Aida and is surprised by what he learns. The Watchdogs confront Senator Nadeer with the suspicion that she might have the Inhuman gene, making Tucker Shockley into an explosive fugitive.
The S.H.I.E.L.D. team launches a rescue mission inside enemy territory after Mace is captured, leading to a showdown with Anton Ivanov. Meanwhile Fitz wrestles with the moral implications of his work.
Fitz and Simmons must tread carefully after they discover that LMD double-agents have infiltrated S.H.I.E.L.D. at the highest levels. While the enemy works to round up Inhumans, Aida moves forward with the next phase of the plan.
Upon entering the Framework Daisy and Jemma find a work where S.H.I.E.L.D. has fallen, Inhumans are hunted, and Hydra runs a dystopian police state. While Daisy works as a Hydra agent Jeffa fights to elude arrest, and their friends appear to play their new roles with no knowledge of who they really are.
While Simmons and Coulson get themselves deeper into the resistance movement, Daisy looks for intel on the location of Holden Radcliffe in the hopes of finding a way out of the Framework. Meanwhile, Mack and his young daughter try to stay under Hydra's radar.
When the Patriot goes in search of a Hydra prisoner, Agent May agrees to become a living weapon to stop S.H.I.E.L.D.'s leader. Jemma tries to motivate S.H.I.E.L.D. by sharing the truth about their reality.
Daisy and May fight to escape from Hydra and elude pursuit after the former agent's change of heart, while Coulson worries about the future of S.H.I.E.L.D. After Aida is critically injured, Fitz sets her final endgame into motion.
With intel on a way out of the Framework Daisy and Simmons must convince their friends to walk away from the world that they know. While Fitz attempts to regain Radcliffe's trust, Jemma takes drastic action after learning about the existence of Leopold's father.
Coulson and May find themselves trapped behind enemy lines after awakening from the Framework, while Daisy, Simmons, and the airborne S.H.I.E.L.D. team must stay alive long enough to come to their aid. Elsewhere, "Ophelia" tries to convince Fitz that she has been acting in his best interest.
The S.H.I.E.L.D. team gains a powerful weapon against Aida when Ghost Rider returns, seeking to take the Darkhold out of our realm. As the agents fight against Aida's many Inhuman powers, Yo-Yo enters the Framework on a dangerous mission to rescue Mack before the virtual world collapses entirely.
