In the milestone 100th episode, "Lois' Sister", Lois' younger sister, Susan (Laurie Metcalf), pays the family a visit and brings with her expensive gifts for the boys, biting remarks for Lois and a cold shoulder for Hal â- whom she has never forgiven for dumping her for Lois. Lois and Susan's competitive relationship takes a turn for the worse when Susan gives Malcolm and Reese her prize '65 Mustang convertible. But when Lois discovers that Susan needs a kidney transplant, she puts her anger aside and offers to donate her kidney to Susan, which Susan only sees as the perfect opportunity for Lois to one-up her.

Gideon makes a secret deal with the Darklighters to get rid of Leo, but the plan backfires when Leo and Piper are both inadvertently trapped in the realm of the dead. Meanwhile, Phoebe and Paige mistakenly believe that Leo and Piper have both been killed, and a worried Chris reveals that he must be conceived before the end of the night or he will cease to have ever existed.

Apu and Manjula are signing up two of the octuplets for Miss Wickerbottom's Pre-Nursery School and after a verbal exchange with Dr. Hibbert, Homer decides they should do the same for Maggie. Because she can't talk, she doesn't pass the initial screening. Afterwards Lisa discovers that even though Maggie can't talk she does show signs of brilliance. Another screening at the pre-pre school shows of her talents and reveals that she has a higher IQ than Lisa. Maggie's new brilliance leaves Lisa searching for a new identity, since she no longer has her status as "the smart one." Lisa tries stand-up comedy, becoming a goth Ravencrone Neversmiles,' cheerleader, rapper, soccer player, cowgirl; none of which workout for her. After she is discovered trying to sabotage her sister's education Lisa leaves home with 2 to her name. She decides to stay at the Natural History Museum, where her family is sure to never find her; however Springfield's "finest" do discover her location and they bring the family to help them find her. An accident gets Marge, Bart and Homer trapped in an exhibit and they look to Maggie to get them out, but Maggie's secret to her brilliance is nowhere to be found.

Hank takes Bobby and the guys on a fishing trip, where they vow to eat only what they catch. A very hungry Bobby befriends the campers next to them, who are a group of hippies. After they feed him half of a hamburger bun, Bobby starts to eat with them. The hippies run out of their supply, and come to Bobby for repayment.

Construction workers discover a skull with bullet hole under the ruins of a disco club burned down in 1978. 22 people died in the fire. Rush and Valens come to the conclusion that the burning of the club was arson, meant to cover up a murder leaving them with not one, but 23 cold cases.

Goren and Eames stumble upon a web of corporate corruption that involves fraud, bribery, identity theft, and a conspiracy to sell lethally contaminated blood products as they investigate the murder of a pharmaceutical salesman.

After arriving home, Tim starts to worry when he learns that Jenny has vanished. Bette travels to New York for an art opening and her relationship with Tina is put to the test. Back in Los Angeles, the sperm donor's girlfriend discovers a lonely Tina and starts to harass her.

Carrie has an awkward meal with Petrovsky's ex-wife and begins to wonder if she can ever live up to his ex. On the streets, Carrie meets some of her fans who want to throw Carrie a party. In New York, Samantha drives Smith away when her sex drive begins to fade, but Smith lets Samantha know that he has strong feelings for her, even when she has no sex drive. Charlotte and Harry finally receive good news about their adoption. Steve and Miranda agree to let his mother live with them after she has a stroke. Back in Paris, Petrovsky ends up slapping Carrie during a fight, and runs into Big, who is there to help her pick up the pieces.

Larry decides to buy a surrogate mother a gift, but it backfires. He tries (and fails) to pass a routine physical and uses it as an advantage. Meanwhile, Wanda constantly observes him engaging in seemingly racist behavior.

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