Andy is forced to confront her father after discovering that he has a degenerative nerve condition that could threaten his independence; Lu treats a pregnant woman whom she subsequently discovers is under investigation in connection with several unexplained infant deaths.

When Lu's (Rosa Blasi) patient receives a desperately needed transplant, Andy (Patricia Richardson) has designs on the discarded liver. Also, when one of Lu's patient's ex-con husband returns home after more than three years in prison, he may be suffering from more than depression. Meanwhile, Andy considers taking her relationship with Dr. Morton (Richard Biggs) to the next level while Lana's (Jenifer Lewis) life is turned upside down when someone from her past returns. Dr. Biancavilla (Brennan Elliott) faces a moral dilemma when a paramedic friend is pricked by an IV drug user's needle.

Lu deals with the schizophrenic mother who takes her five year old girl who suffers from epilepsy off of her medications in favor of a ""ketogenic diet"" which has stopped all the seizures. Additionally, Andy and Lu have a friendly competition when each one of their patients is studying for a spelling bee. Andy also has to adjust to spending her first Christmas holiday without the kids.

Andy is surprised when ex-husband Les shows up unexpectedly after Lizzy has her knee operated on after a soccer accident. Les learns that his wife is dating Milo. Andy invites Milo to dinner to meet Les and is shocked by the tragedy that ensues. Andy meanwhile treats a prominent judge for hearing loss and has trouble figuring out the cause of it.

Dr. Campbell is asked to write an endorsement for a new book about female heart health written by a friend and patient. After the author dies of a heart attack, her husband refuses to publically announce her cause of death because he fears it would hurt sales of the book even though her diet had nothing to do with her death (she had heart disease). Lu is shocked when three high school girls come into the ER with similar and shocking symptoms that point towards poisoning.

With Christmas only a few days away, Lana goes on a frenzy decorating the clinic and organizing a Secret Santa gift exchange. However, when a plan to set up Peter and Kayla backfires, she has a lot of explaining to do. Meanwhile, Lu delivers a virgin surrogate mother's baby but when the parents find out something about the baby, they do the unthinkable. Also, Andy must find a young girl who may die if she doesn't get treated for a deadly disease she may have.