When a patient suffering from anorexia can’t gain the necessary weight needed to survive heart surgery, Claire suggests they perform an experimental surgery which Melendez strongly opposes. Shaun worries Glassman’s refusal to walk the hospital floor will keep him from being discharged and tries to persuade him to ambulate. Meanwhile, Shaun and Lea change the terms of their current relationship.

Dr. Shaun Murphy and Dr. Alex Park treat two patients who collapse at the local airport and whose symptoms point to an infection that may become airborne. The staff races to contain the infection before it spreads to the rest of the patients in the ER, resulting in a hospital quarantine during the holidays.

Dr. Claire Brown faces complications at home and work as she prepares to lead her first surgery. Meanwhile, a sports fishing accident challenges the rest of the staff as they look to treat the fisherman’s injuries without damaging his prize catch.

The doctors must treat a 25-year-old runner who is suffering from severe swelling; two 16-year-old cancer patients are dating; Dr. Shaun Murphy and Dr. Carly Lever work toward intimacy.

The city of San Jose is rocked by a massive earthquake that puts the staff of St. Bonaventure Hospital on high alert as they race to assess the damage and account for the safety of their colleagues and friends. Meanwhile, Dr. Neil Melendez and Dr. Aaron Glassman are attending a charity event when their lives are threatened by the earthquake.

Dr. Murphy treats a patient who has an illness that is not only unpredictable in nature, but also unlike anything he or the team has seen before. Dr. Claire Brown continues to work through her grief, still reeling from Dr. Neil Melendez's death.

Shaun has a hard time balancing his fears and concerns about potentially jeopardizing Lea's health and wanting to be with the woman he loves. Claire looks for a way to grieve Melendez's death. Park and Mia discuss their future together.

Lim is challenged by the unique circumstances surrounding a pregnant patient with an aggressive tumor. Elsewhere, after misdiagnosing a patient, Claire makes a disconcerting discovery about certain practices at the hospital.

The St. Bonaventure team travels to Guatemala on a surgical mission to help patients at a rural hospital. Once there, the team faces a small community that is in desperate need of their help but are assigned the daunting task of identifying who they can help most. And while Shaun seems to be thriving in Guatemala, Lea is still struggling with the loss of her baby.

Shaun and Lea's upcoming engagement party has everyone in a festive mood; a young single mother learns her son may have contracted his cancer from a surprising source; Mateo finds out if his previous issues in America will be resolved.

The team treats a famous marriage counselor after she injures her ankle from falling, but when she offers relationship advice to them, Dr. Morgan Reznick quickly spots that their patient might be experiencing something far more serious. Meanwhile, Dr. Audrey Lim is determined to get to the bottom of what really happened in the OR during her surgery and sets off on her own internal investigation.

Shaun and Lea adjust to parenthood as they debate the importance of schedule and routine for Steve. Meanwhile, Shaun takes on his first case back at the hospital with two baby patients in need of the same heart.