Kyle needs a kidney transplant and Cartman is discovered to be the perfect donor. Cartman gladly offers his kidney to Kyle, for the price of $10 million. Stan, depressed about the inevitable loss of his best friend decides to take matters into his own hands and get Cartman's kidney for Kyle.
A substitute teacher has come to class after Mr. Garrison is fired for having charges against him soliciting sex from a minor (Cartman, from Cartman Joins NAMBLA). Stan, Cartman, and Kenny jerk around with him, each one pretending to be the other. Cartman laughs so hard after this that he squirts milk out of his nose when he laughs too hard, even when he isn't drinking any. Kyle is not there because he is suffering from kidney failure, and the teacher gives the class an assignment to make Kyle a get-well card (Butters ends up becoming that card).
Stan visits Kyle to bring Butters so he can sing his get-well song. Sheila mentions Kyle has always had diabetes, and has failing kidneys. Sharon suggests that Sheila try the New Age healing to cure Kyle. They go to the store of "Miss Information", the new mystical woman in town, who tells them that Kyle’s illness is being caused by “mysterious toxins” in his system. She then prescribes a series of herbal medicines to help him.
Though they actually make his condition even worse off, she convinces the customers that they are gradually healing him in a non-immediately apparent way. Soon the whole town becomes enamored with her remedies and buy such nostrums as "Cherokee hair tampons" from two supposed Native Americans (played by and modeled after guest stars Cheech and Chong). Later, when they are seen, they look more Mexican than they do Native American.
In the subplot, Mr. Garrison, after having been fired from the school, takes up a new career as a romance novelist. He writes a novel entitled “The Valley of Penises”, and goes to “Harequin Romance” (a takeoff of Harlequin Romance) to get it published. It turns out that the book uses the word “penis” 6,083 times, making it one of the gayest books ever written - to Mr. Garrison’s chagrin. However, he manages to persuade the publisher that his target audience is women, and it's only natural that they would be interested in descriptions of penises (as opposed to female anatomy), securing himself a publishing deal.
Stan, not trusting Miss Information’s medicines, goes to inquire Dr. Doctor over the matter. The doctor tells him that Kyle will die unless someone else who has the AB negative blood type donates him one of their kidneys. Unfortunately, there is only one compatible donor available - Cartman. While Stan tries to convince the public that Miss Information’s medicines and healing techniques are not really affective - to which she insists that Dr. Doctor is only after money, unlike herself. She’s all about using natural remedies, even though she charges $100.00 minimum per item - he also tries to get Cartman to donate one of his kidneys. Since this is Kyle whose life is at stake, Cartman refuses - unless he is paid ten million dollars for it. Even when Stan, Kenny, Butters and Timmy sneak into Cartman’s house and try to remove one of his kidneys themselves. Inside they sneak past Fluffy, who wakes up by Butters stepping on his tail. Cartman, hearing Fluffy's squeals, hits Fluffy to make her shut up, then goes back to bed without noticing the others. It turns out to be a futile effort, as Cartman, not taking any chances, is wearing a “Kidney Blocker 2000”.
After seeing Kyle, who by now is on the verge of death as a result of Miss Information's ineffective treatments, the “Native Americans'” conscience gets the better of them, and they finally spill the beans to Mrs. Broflovski and the rest of their customers, saying that Kyle really needs to see a doctor about his condition, and also revealing that Miss Information is a total fraud. They aren’t even Native Americans - they’re Mexicans, but were told to pretend to be Native Americans because Miss Information thought no-one would want to buy medicine from Mexicans. Everyone, especially the women who bought the Cherokee Hair Tampons, is horrified by this revelation, and they promptly beat Miss Information to death. Meanwhile, Stan comes up with a plan to trick Cartman into donating his kidney to Kyle.
When Cartman awakens the next day, he finds that his Kidney Blocker has been destroyed, and there’s a thick red liquid all over his bed. He heads over to Stan’s house, retrieves his kidney, and marches over to the hospital, demanding that they return the kidney to its rightful place. However, Liane had actually opened the blocker, and put ketchup in his bed to trick him into thinking they’d removed his kidney. Cartman then signs a release form, which actually permits Kyle to take his kidney. It is never revealed where the kidney which Cartman took from Stan came from, but it can be assumed Dr. Doctor gave it to him. Kyle makes a quick recovery, and Mr. Garrison gives him a copy of his newly published novel as a gift.
Though Cartman is initially angry at being tricked into losing his kidney (especially since it saved Kyle's life), when Kyle laughs and squirts milk out of his nose, Cartman laughs, stating "You got the crappy kidney," to Kyle.