The Planet Expresscrew has been hired for their 100th delivery to deliver nitroglycerin in a soufflé form made by Elzar. In the meantime Bender wants to celebrate and decides to plan the party "of the millennium". Mrs. Astor, the person they are to deliver it to, lives in the Waldorf Asteroid, however due to the soufflé's instability, it needs to be handled with care. Since Bender is gyroscopically stable, he insures the soufflé does not fall or wobble too much. The Planet Express ship turns and rotates many times in the asteroid belt but Bender is able to keep stable. At the Waldorf Asteroid, when they came to a rickety bridge, Bender has to run around the planetoid twice, to hold the soufflé stable and then jump over the bridge. He lands safety near the house, while the rest of the crew just walk over the bridge. The rest of the crew hides behind Bender as they expect the soufflé to explode, but is does not as Mrs. Astor only takes a bite and then throws it to the dogs where it then explodes. Mrs. Astor discovers that the professor is a Farnsworth and is impressed and because Fry is his uncle she invites both Fry and Farnsworth to her fundraiser, where only the best families come.
At the fundraiser Fry has invited Leela. Mrs. Astor shows a film about the Land Titanic - the largest street-going vessel ever built - which sank in 2912 with Mrs. Astor's husband aboard. This year the fundraiser supports mutants' education below the surface. They see a film about the Mutants in the sewer and how they could use the money at Brown University where they use their skills to build their own society. Mrs. Astor comes down to Leela and says it is all just to keep those Mutants busy so they will not come up to the ground in revolt and demand equal rights. Fry accidentally mentions that Leela is not an alien but a mutant who illegally lives on the surface and Leela - mad at Fry - is banished into the sewers.
From the start Leela hates it down in the Sewers, but her parents try to cheer her up. In an attempt to rectify his mistake, Fry, along with the rest of the crew (except Bender who is ready to party), go to the City Hall to do something. Finding out that they've harbored a mutant, Mayor Poopenmeyer sentences them to two weeks below the surface. Meanwhile, Bender organizes a giant party with a lot of people. When the crew have reached the sewer they meet Leela and Fry says that he believes living beneath the surface will be a good thing as he will now understand what being a mutant feels like. Leela is angry at this and states that if he wants to understand he should jump in Lake Mutagenic and become a mutant. Fry comes up with an excuse not to and Leela is left angry at him. While walking the sewers, the crew stumble on the Land Titanic, a land bus in the shape of the Titanic which struck a mail box and sank beneath the surface. After looking through the ship for a while, they find a safe containing a rare Quantum Gemerald and a list of passengers on board the vessel. The crew decide to stay in one of the cabins. Leela asks her parents if she was too hard on Fry and her parents try to cheer her up. Bender keeps having a party. However, when he realizes that he misses the rest of the crew, he orders everyone out and wallows in self-pity. Fry, unable to sleep, walks towards the toxic lake about to jump in. Leela, also walking around, tries to stop him but Fry jumps in anyway. She takes a boat out on the lake and pulls him out, only to find that he is now severely mutated.
Having enough of the segregation, Leela, along with Fry and the rest of the crew, start a revolt against the street dwellers. While plotting attacks on New New York, Fry returns to the surface for Bender, so that he can bend the Western sewage system and resend all the sewage back up the pipes. This leads to the streets of New New York being covered with sewage.
Mrs. Astor demands something to be done and the Mayor orders an Antarian to send all the waste to Madison Cube Garden. Leela leads the mutants up onto the surface and demands equal rights. Mrs. Astor orders her butler to fire a missile, which misses the mutants and hits the Madison Cube Garden, sending a tidal wave of sewage at them. Just before they are covered, Fry appears and uses the jewel to separate the sewage (in a way a lot like Moses parting the Red Sea). Fry reveals to Mrs. Astor that they found the wreckage of the Land Titanic, along with a list of passengers, which included mutants. Fry reveals an old and aged mutant, revealed to be Leela's grandmother, who was a young worker on the Land Titanic when it sunk. She reveals that Mr. Astor selflessly gave his seat up for her and her mother. Touched by this revelation, Mrs. Astor asks for the mutants to be allowed to the surface, which Mayor Poopenmeyer easily allows. Leela states she now has the stomach to kiss Fry for all he's done. When they kiss, Fry returns to normal and the body of another mutant is formed. It is then revealed that Mr. Astor fell into the toxic lake and mutated many years ago. When Fry jumped into the lake, he became lodged in Mr. Astor's mouth. Mr. and Mrs. Astor are united once again and hug. The crew returns to the Planet Express headquarters with Leela's family and celebrate their 100th delivery by dancing.
According to David X. Cohen, the 100th episode may had to serve as a series finale, depending on Comedy Central. A photo of Mike Rowe's production script has been uploaded by Mike Rowe onto his Facebook page. The cover of the script highlights it as the 100th episode, as well as revealing the title, "The Mutants Are Revolting", indicating the episode contains mutants other than Leela, including Fry after exposing himself to the irradiated lake in the sewers, becoming a horrendous mutant (as shown in the Comedy Central preview trailer).