Alex and Maggie discover that one of the car crash survivors they're treating has breast cancer, and is a match for their cancer study. Meanwhile, Dana's resolve to re-certify in Trauma is tested when Dawn pushes her to treat a mangled motorcyclist, and Charlie is pulled into surgery before his arm is completely healed.
It's a not-so-Happy Birthday for Alex, who's still reeling from her split with Charlie. To make matters worse, she makes a promise to a young girl, whose own birthday is derailed by her father's sickle cell crisis. Charlie treats a paranormal skeptic, only to discover this supernatural naysayer has a haunting of his own. And Cassie confronts her inner fear of parasites with some exposure therapy, as she treats a brother/sister duo riddled with every infestation.
Tempers flare as Dev's med school rival, Billy Scott arrives at Hope Zion, while Alex breaks the rules and puts her job in jeopardy to help Manny save the life of an at-risk youth, and Charlie and Maggie treat an 1812 War re-enactor, whose complications align with the historical character he's playing.
Charlie and Manny go toe-to-toe while treating two star-crossed lovers who are having an affair. Maggie and Dawn's different approaches to medicine are put at odds while treating a dad with a ninja star injury and his worried young son, while Dawn also deals with her bid to get back the Chief of Surgery position, and Maggie evaluates the residents.
When a John Doe comes into the hospital after being struck by a subway train, it's a race against the clock to save his life, but things take a more dramatic turn when Charlie realizes that the man is no John Doe, but "The Great" Randall Crane. Maggie attempts to leave her past behind, but that proves impossible when Sydney Katz comes back to town, urging Maggie to put her pregnant sister in the now-defunct cancer study. Away from the hospital, Alex takes her mother to their family farm in the wake of Martha's diagnosis, only to find out that Martha wants to take her ...
While planning her mother's memorial service, Alex treats a young chronic kidney patient who has a "savior sibling" who is going to donate one of her kidneys, but when she presents with a cardiac virus, the sick sister becomes the savior. Meanwhile, Maggie and Sydney rediscover and rekindle their relationship while treating an interesting young couple.
Alex treats a meditation instructor who wants to be awake in surgery. Cassie treats a hyped-up extreme fighter. Charlie walks out of an operation on a man he met earlier on the road. His psychiatrist shows him that he's confusing ghosts for the living.