At Springfield Elementary, Lisa is presented with a brain teaser, which she is unable to solve. Following this incident, Lisa finds herself unable to perform simple tasks, such as remembering the combination for her locker, her saxophone technique, and forgetting to complete a homework assignment (as she'd stayed up late the previous night trying to complete the brain teaser). Later, Lisa tells Grampa about her recent cognitive problems. He seems to recognize this, and tells Lisa about the "Simpson Gene", which apparently causes all members of the Simpson family to gradually lose their intelligence as they get older. To prove his point, Grampa shows Lisa a picture of young Homer as a spelling bee champion, and a series of old report cards of Bart's which reveal that her brother was extremely intelligent when he was young, before slowly degrading into the ignorant hooligan he is today. Presented with such evidence, Lisa soon accepts this as her fate.
Meanwhile, Jasper visits the Kwik-E-Mart and attempts to empty the freezer containing ice cream in order to freeze himself, with the intention of being defrosted sometime in the distant future. Apu decides to take advantage of this unusual situation for financial gain by advertising the frozen Jasper as "Frostillicus" and re-branding the Kwik-E-Mart as the Freak-E-Mart. The convenience store becomes more profitable as a tourist trap, until the freezer's cooling system fails, causing Jasper to defrost and walk away. Fearing that he will lose customers, Apu turns the Freak-E-Mart into a combination of a convenience store and a strip club and re-renames his store to the Nude-E-Mart.
After watching Bart and Homer eat candy they had hidden in the sofa, Lisa imagines her future, which involves her being married to Ralph Wiggum, being morbidly obese, speaking in a Southern accent, and having many children. This frightens Lisa, causing her to appear on the TV news program Smartline to tell the citizens of Springfield to treasure their brains. As she does this, Homer decides to prove her wrong, and contacts the entire extended Simpson family (which the men all look and sound like Homer) to visit, so he can prove that at least some of the family are intelligent. However, when they arrive, Homer realizes they're also unsuccessful, unintelligent people, which only depresses Lisa further and causes Homer to send them home.
However, before they leave, Marge urges Homer to talk to the Simpson women. Reluctantly, he talks to them at her request and he discovers that the women are all successful: a doctor (who bears a striking resemblance to Lisa), an architect, an environmental lawyer, and a sales coordinator of a large company specializing in bunk and trundle beds. Dr. Simpson reveals that the defective "Simpson Gene" only exists in the Y chromosome, meaning that it only affects the male family members and not the females. As a result, she will be successful like them. Lisa is relieved that she is fine and she will not suffer the "Simpson Gene", because of her gender. However, Bart bemoans that he will be an unintelligent failure in life, like the males because he inherited the "Simpson Gene". However, Homer reassures him that he will be "a spectacular failure". Bart gladly accepts this and returns to playing with the other Simpson men (where they wear pots as helmets and hit each other's heads).
The episode ends with Lisa finally being able to solve the brain teaser she was unable to finish earlier in the episode with a Homeresque "Woo-Hoo!", before correcting herself with a restrained "splendid.". This proves that while she may not suffer the defective Simpson Gene, Lisa is still a Simpson.