Homer, Bart, Lisa, Maggie and Grampa are watching a Dr. Nick program (who didn't realize his patient was pregnant and even mistook the umbilical cord for an astronaut tether) when Marge turns off the TV and tells them that it's her mother's eightieth birthday and the family should visit her. Homer doesn't want to go, claiming that the Bouviers hate him, only agreeing to go for Marge. At Jacqueline's house, while watching slides which include Marge's father, Clancy, the question about how he died is brought up, something that Marge, Patty and Selma never found out about. Jacqueline decides to reveal the truth: her husband died of lung cancer but didn't say so before because back then, people were reluctant to admit it (and she didn't stop Patty and Selma's smoking because she thought it made them look cool). This revelation shocks Patty and Selma, who decide to quit smoking once for all and burn all their cigarettes, which unfortunately causes Jacqueline's house to burn down.
At the DMV, Patty realizes how hard it is to quit smoking after years of addiction after thinking she was having a stroke. She also realizes that Selma is not affected by the sudden change of habits, and decides to consult Dr. Hibbert. At the hospital, Patty discovers that Selma relapsed ten minutes after quitting smoking. Patty gets angry and has a fight with Selma that leads to Patty staying at The Simpsons house for a while.
Homer doesn't want Patty there and he quickly gets annoyed by Patty's snoring while he and Marge are trying to have sex. The next morning, he walks into the bathroom while Patty is taking a shower (thinking it is Marge), which makes him pour bleach in his eyes (and Bart's) to save him from seeing the sight. Meanwhile, at the apartment, Selma has a hard choice: quit smoking and reconcile with Patty or carry on smoking and lose her sister's respect. She decides to quit smoking and they reconcile.
At the end of the episode, Patty and Selma return to their apartment and quickly notice in the absence of cigaratte smoke the noxious odors in a small apartment that include two aging women, a baby and an iguana. They quickly take up smoking again to cover up the odors, though are unsure if it will be a happy ending. A montage of their life and death through smoking is shown as Rick Astley's "Together Forever" is heard in the background. Even after their death, cigarette smoke is seen rising from their graves.
In a secondary plot known as "Maggie's Extraordinary Animal Adventure", Maggie befriends a squirrel who introduces her to other animals such as an owl, an opossum, and a parrot (which is revealed to belong to Duffman). However, Cletus captures the opossum for dinner and puts the captive animal under his dog's surveillance. Maggie makes a plan to fight against the Spucklers and free the opossum by assembling an army of animals. With help from Plopper the Spider-Pig, Maggie and the animals are able to free the opossum and defeat Cletus and his dog before going their separate ways, with the parrot returning to Duffman, revealing that he has picked up some of Cletus's phrases.