Before Allen Conner can process losing his job as the head of Infectious Diseases at Bethune General Hospital (Beth-H), a massive explosion tears through the basement. Though he and Griffin work brilliantly together to treat those caught in the blast, the damage is catastrophic. Striking new ER resident Peter Cutler recruits Mel in aid of a foreign agricultural worker. Chief-of-Staff Linda Tuttle looks for a scapegoat in the wake of the explosion, while the downstairs staff grapple with loss, and Allen pursues a new position as an ER doc at Beth-H.

After Melissa Conner performs what should be a straightforward surgery on firefighter Renee Hudson, Renee is left in mysterious and agonizing pain. As Mel and Jerry retrace their medical steps trying to find the cause, the cracks in their relationship are exposed. Allen's first day in ER is complicated by the strange and unhappy behavior of Tyson "Pitbull" Danko, and Allen and Cutler need to work together in order to keep Pitbull in hospital long enough to find out whats really wrong with him. Griffin and Zoe pull together to help a still-reeling Kanaskie eradicate a bedbug problem at Beth-H.

Griffin is forced to account for his actions when a patient dies while under his supervision.

Allen performs an extraordinarily rare and dangerous medical procedure, and Zoe's mother turns up at Beth-H unexpectedly.

Exhilarated by her new romance with Cutler, Mel is uncharacteristically reckless in the operating room.

As Cutler tries to figure out where he stands with Mel and at Beth-H, a woman mysteriously goes into toxic shock and she and her husband must face the meaning of sacrifice. Mel catches Griffin involved in illicit activity and refuses to believe him when he swears he's clean. Allen butts heads with the new Chief of Staff, while Sandy learns a valuable lesson treating a prisoner admitted to Beth-H.

When a peculiar woman turns up at Beth-H complaining of a migraine, Allen quickly discovers there is much more going on with her than a headache and he'll need to employ all of his ID (Infectious Diseases) skill in the ER. Mel reattaches a reluctant construction worker's severed hand while also contemplating what Cutler's move to Dallas means for her. A patient of Sandy's is refusing to eat, and Griffin's misguided effort to help nearly leads to disaster.

Mel tries to save an EMT after her wife dies; Griffin reconnects with Hugh; Allen asks Kanaskie to give Griff his job back; Cutler tries to protect an explorer.

Griff's behaviour stops Mel and Cutler from going to Dallas; Sandy insists the Conners address Griff's drug problem; Mel and Dr. Jake Epstein fight over a patient.

Sandy is in critical condition after a car accident; Zoe finds Griff and brings him to Beth-H; Cutler tries to treat a boy with disturbing behaviour; Griffin finally asks for help.