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- The staff of the L.A. County Hospital emergency room treats patients under difficult circumstances.
- A high-tech intelligence operative, enhanced with a super-computer microchip in his brain, aids an elite government cyber-security agency in special missions.
- Gabriel and Riley must rescue the kidnapped member of CyberCom who invented the chip implanted in Gabriel's brain before the top-secret technology falls into the wrong hands.
- Gabriel and the team go to Texas to help contain a deadly, quickly spreading virus and identify patient zero.
- CyberCom investigates a terrorist suicide bombing at a United States Marine Corps base and learns that new, chemically undetectable bomb material is being consumed.
- Gabriel and Riley adopt the guise of Secret Service agents when they travel to war-torn Syria in order to rescue a pair of journalists being held hostage there; Riley's past is revealed when she is forced to work with her former boyfriend.
- A CIA agent goes rogue with very important information from the CIA, which results in the death of a M.I 6 agent. When Gabriel is brought to the case they find out that Mei Chen is able to hack into his head.
- The daughter of a senator in Mexico is kidnapped by a cartel; Lillian uncovers a connection between her father (Peter Coyote) and the cartel.
- While in Bolivia with Riley to protect a presidential candidate from assassination, Gabriel is shocked to learn his best friend is the suspect.
- Riley and Gabriel are shocked when the identities of sleeper agents embedded in the U.S. government are revealed.
- Gabriel, Riley and Nelson have to work with a young hacker to destroy a worm before it causes a nuclear incident in Los Angeles.
- Cybercom is under attack, as an interference with the chip makes Gabriel suffer from amnesia.
- Gabriel and Cybercom investigate when artificial intelligence scientists are infected and killed by microscopic robots.
- After being framed by Mei Chen with the murder of the Deputy Director of the FBI, Gabriel has to run against time to prove his innocence.
- Gabriel, Riley, Lillian and the rest of Cybercom try to stop a neurotoxin that could destroy half of San Francisco before it's too late.
- Christa begs Neal to perform a surgery that will ensure a patient's reproductive future; a patient fights with Mario.
- Amid the chaos and exhaustion of working 36 consecutive hours in Code Black, the doctors must deal with Margaret O'Brien (Gail O'Grady), the distraught mother of two sons who are in a devastating car accident. Also, Mario bullies Angus into performing an unnecessary operation but lets Angus take the blame when Leanne finds out.
- Dr. Leanne Rorish puts her new first-year residents right to work at Angels Memorial Hospital, Home to the nation's busiest ER.
- A new surgical attending Cole Guthrie (Cress Williams) joins Angels Memorial with the help of his estranged father and clashes with Leanne over their contrasting approaches to medicine. Also, Christa has a crisis of confidence in the middle of a procedure on her first infant since the loss of her son.
- Neal clashes with his father, Dr. Peter Hudson (Daniel Gerroll), who is a neurosurgeon, over how to treat his gravely ill mother, Asra Hudson (Roma Chugani), whose mysterious symptoms force Angels Memorial to quarantine Trauma One.
- Leanne must deal with the difficult decision of whether to save Tom Moreno (Michael Trucco), the police officer who helped her during her family's accident, or his shooter, who has more serious injuries. Also, when Malaya's pregnant ex-girlfriend, Carla Niven (Shiri Appleby), arrives at the hospital with pain in her arm, Malaya is shocked by her MRI results.
- Christa has her busiest shift yet when she is responsible for all emergencies at Angels Memorial that occur outside of the E.R. Also, Mario bonds with an older gay patient with a heart arrhythmia who's living with HIV (Stephen Spinella), Malaya starts a bone marrow drive for Carla (Shiri Appleby) and Leanne refuses a date with Cole (Cress Williams).
- Angus uses his background in psychology to help a woman who doesn't remember how she injured herself and others. Also, when Christa bonds with an illegal immigrant whose son is diagnosed with cystic fibrosis, she becomes determined to help the woman find long-term care for her son in the U.S.
- When the lead actor (Alton Fitzgerald White) of the musical "The Lion King" tour arrives at Angels Memorial with a throat infection, Leanne gives him a diagnosis that puts both his career and life in jeopardy. Also, the doctors and the cast of "The Lion King" help a 17-year-old boy deal with the difficult decision of taking his father off life support.
- Leanne is rattled at the thought of losing Jesse as he fights for his life after suffering a massive heart attack. Also, Mario asks the residents to cover for him when he searches the city for a patient's son, disobeying Neal's direct order not to leave the hospital. Cress Williams returns Cole Guthrie.
- The doctors find their own lives in danger when they arrive at the scene of a massive multi-vehicle accident on a highway covered in thick fog. Also, Jesse's confidence is shaken following his heart attack, while Carla's (Shiri Appleby) condition becomes critical.
- Leanne visits a prison to confront the drunk driver who killed her family; a patient makes Malaya feel uncomfortable.
- Angus is conflicted when his older brother, a superstar ER doctor, returns to Angels Memorial with hopes of acquiring an attending position; Christa's feelings for Neal continue to grow; a patient becomes fixated on Malaya.
- As the doctors treat patients from the chaotic multi-vehicle accident, a love triangle begins to build between Mario, Angus and Heather. Also, when Malaya learns that Carla is at the hospital, she goes against Carla's wishes and stays by her side during the delivery of her baby.
- The doctors are questioned following a violent incident inside the hospital that leaves two doctors gravely injured. Also, Neal and Christa make their relationship to the next level after officially disclosing their romantic relationship to HR.
- Christa must put aside her personal feelings for Grace and work with her to treat Brody, (Cameron Boyce), a patient who claims to have been abused at a camp for troubled teens. Also, Grace is surprised when Campbell asks her out.
- Christa becomes insecure in her new relationship with Neal when his ex-girlfriend, Dr. Grace Adams, returns to Angels Memorial after spending a year volunteering in Haiti. Also, New York Giants Pro Bowl wide receiver Odell Beckham Jr. comes to the ER to convince his stubborn high school football coach, Pete Delaney, to have life-saving surgery.
- Mario confronts Angus about his Adderall abuse and Christa is surprised to learn how romantically involved Neal and Grace were before she left for Haiti. Also, Dr. Mark Taylor (Kevin Dunn) returns to help Leanne find the money in their budget to keep Jesse and the nurses from walking out.
- Col. Ethan Willis joins the team as part of a program in which the Department of Defense sends doctors to hospitals to teach new techniques.
- Willis must help a promising soccer player make a life-altering decision after he's seriously injured, and another patient's hesitation to share that she's transgender makes it difficult for the doctors to diagnose her severe abdominal pain.
- Willis defies Campbell's orders when he helps Mario and Heather perform a radical procedure on a maintenance worker stuck under a boiler that exploded. Also, Angus' father, Dr. Desmond Leighton (Steven Culp), tries to seize Power of Attorney over Mike, who is still in a coma, even though Mike granted that right to his brother, Angus.
- On Halloween night, Willis, Noa and Elliott rush to the scene of a fire at a haunted theater, where Dr. Nolan (Kathleen Rose Perkins) and her boyfriend's son are trapped.
- The Angels Memorial doctors treat victims caught in a landslide, and a group of children come in from a camping trip with measles putting the entire ER at risk. Meredith Baxter and Eric Roberts guest star.
- The doctors treat cult members who unwillingly survived a mass suicide attempt, and Mario decides to connect with his late father's girlfriend.
- Malaya must inform a college student that she's been raped, while Willis and Campbell argue over a terminally ill woman who wishes to die on her own terms.
- Willis and Campbell are sent to a Russian submarine in U.S. waters to treat a sailor badly wounded during an explosion, and violent convicts injured during a prison riot descend upon Angels Memorial.
- When a police officer arrives at the emergency room with an explosive bullet stuck in her leg, a risky operation is needed to be performed by Wills, Leanne and Jesse; a magician having difficulty breathing comes to Angel's memorial for help.
- A city-wide blackout leaves Angels Memorial without power or back-up generators.
- The doctors must treat Campbell's 13 year old daughter when she arrives at the hospital after a seizure caused by spina bifida; a deaf work addict and her translator seek medical assistance ate their car rolls over into the Los Angeles River.
- Against Campbell's orders, Leanne uses the hospital helicopter to reunite a family one last time.
- Mario follows Willis to a construction site to save two brothers trapped in a crane 300 feet above the ground.
- Guthrie considers an experimental surgery to treat his Parkinson's while adjusting to his new position as the hospital chaplain.
- A viral outbreak jeopardizes the doctors and patients of Angel's Memorial.
- The doctors of Angel's Memorial partner with Center for Disease Control and Prevention to find an antidote for the viral outbreak.
- A drug bust-turned-shootout tests the bravery of all doctors as they race to save a girl in the crossfire. Willis shifts his career focus to field medicine. Leanne faces the new but tragically familiar challenges that parenting presents.