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.

When Dr. Abbott's dementia-plagued, elderly godfather (guest star Luke Askew) confesses to a murder that took place 30 years ago and reveals that Abbott's father was his accomplice, Abbott and Dr. Brown join the investigation in an attempt to find out what really happened and clear the men's names. Meanwhile, Ephram can't seem to keep Amy (Emily VanCamp) far from his thoughts, causing major problems in his burgeoning relationship with Laynie (Nora Zehetner). Dr. Brown butts heads with Ephram's new piano teacher (guest star Ian Vogt) over what is best for Ephram.

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.

When Andy's relationship with Delia is threatened after he breaks his promise not to date Linda Abbott, he decides to take his daughter on a special bonding trip to regain her trust. Andy is also surprised by Ephram's emotional reaction to the relationship with Linda. Meanwhile, Andy finds himself in a tough spot when a woman patient wants to get pregnant through in-vitro fertilization with sperm from her first husband, who is now dead, but her second husband is having a real problem over the matter. The Abbott family is still in turmoil when Amy decides to live with Edna and Irv, rather than playing by her parents' rules.