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.
Picking up in the bloody aftermath of last season's cliffhanger, Alex battles fate to save the life of a young woman caught in the crossfire. After Charlie catches a bullet in the arm, the doctor becomes the patient. Dana's patience is tested by an obstinate male stripper named Doctor Destiny.