A heartbroken Ephram finds himself the odd man out as Amy prepares for Colin's homecoming. Meanwhile, Andy and Dr. Abbott join the town in a debate over the use of medicinal marijuana after a large quantity is discovered in a deceased woman's greenhouse; and Andy provides medical guidance to Nina after her son's teacher suggests she put him on Ritalin.

Resentful at being forced to accompany Andy and Irv to a remote lake cabin, Ephram takes a small boat out alone and his inexperience leads to a serious accident and a night of terror for Andy. Meanwhile, Colin and his parents must decide whether to allow Dr. Brown to perform a second dangerous surgery; and Nina confronts her husband Carl after she accidentally discovers he is having an affair.

Andy's well-intentioned plan to give Ephram more free time by hiring college student Madison Kellner (guest star Sarah Lancaster) as a caretaker for Delia ends up making things worse when Madison treats Ephram like a child, as well and embarrasses him in front of Amy. Meanwhile, Andy's concern for Colin's alcoholic father (guest star Michael Flynn) blinds him to Nina's struggles with her divorce proceedings. Dr. Abbot continues to clash with his sister, Dr. Linda Abbott, when she tries to take over his office and the difference in their personalities and medical philosophies becomes alarmingly clear.

Horrified to discover that Ephram and Madison are involved, Dr. Brown stops short of firing her, but Madison decides to quit leaving the Browns to a very unhappy holiday, especially when Delia discovers another troubling relationship - between her father and Linda Abbott. Stressed by Thanksgiving with his cantankerous mother-in-law (guest star Betty White), Dr. Abbott reacts badly when Amy brings Tommy (Paul Wasilewski) to Thanksgiving dinner. Finally pushed to the breaking point, Amy runs away from home.

Ephram is horrified and heartbroken after he impulsively tells Madison (guest-star Sarah Lancaster) that he loves her and she doesn't reciprocate. Meanwhile, Linda naively agrees to watch Delia overnight so that Andy can accompany Ephram and his piano teacher, Will (guest-star James Earl Jones), to a jazz competition in Boulder, and Amy breaks up with Tommy (guest-star Paul Wasilewski) after realizing she might not be able to trust him again.

Against Andy's better judgment, ex-sweethearts Ephram and Madison decide it would be in Delia's best interest if Madison resumed her job as Delia's babysitter. Meanwhile, Amy contemplates going off her anti-depressant medication after Linda suggests she might be ready and Bright anxiously awaits his college acceptance letters.

Andy finds himself at a loss over what to do when Delia naively stumbles upon Nina's vibrator and starts asking questions. Meanwhile, Ephram attempts to write Amy a love letter to show her the extent of his feelings. Amy makes it her mission to make new best friend Hannah (Sarah Drew) popular. Meanwhile, Harold and Rose question Bright's euphoria over being selected "employee of the month" and decide it's time for some parental intervention.

Dr. Abbott becomes worried that his son Bright is settling too little in life when taking a job at a restaurant. Lastly, Andy treats a patient who needs a transplant, but won't tell his wife.

Amanda decides to send her husband to a very nice treatment facility causing Andy to collapse as a result of stress and guilt over what has happened between him and Amanda. Meanwhile, Amy continues to give Ephram the cold shoulder for lying about Madison, Also Edna builds a writing room for Irv.

Jake's visiting accountant brother Brian (guest-star Tom Parker) from LA says he sees no future for Jake and Nina, prompting Jake to seek advice from Andy. Also, accepted at Princeton, Amy assumes that her father secretly sent in her application. Lastly, health issues create tension between Rose and Harold, but the tension turns to fear when Harold finds out that Rose has a 3-centimeter long tumor.