Cartman's favorite restaurant, Kentucky Fried Chicken, has been shut down and replaced by a store that sells medical marijuana to cancer patients. Cartman will do anything to get his beloved fried chicken back. Meanwhile, Randy gives himself testicular cancer so he can get a prescription card to buy pot.
Stan, Kenny, Kyle and Cartman are at soccer practice, during which Cartman yet again manages to avoid playing by claiming he has a stomach ache, much to the annoyance of the soccer coach. After soccer the boys are picked up by Randy who takes them to KFC during which, Kyle points out that Cartman only goes to soccer on Friday because of the fact they go to KFC afterwards. However, the boys are shocked to realize that KFC has been replaced by a medicinal marijuana store. Realizing that pot is now legal, Randy is overjoyed and attempts to purchase some, only to be told that he would need a doctor's prescription. Cartman meanwhile is infuriated by the fact that the only KFC in South Park is now gone.
Randy rushes to the doctors in the hope of getting a prescription for the marijuana for being healthy, however the doctor pointedly informs him that only those who are sick are allowed the prescription, mainly AIDS and cancer patients. Randy spends the next few days attempting to give himself cancer through assorted means such as tanning, smoking, and taking X-RAYS just so he can obtain marijuana legally. He eventually purchases a book about cancer, using it in the hopes that it will give him pointers. At last he finds out that one of the most aggressive types of cancer is testicular cancer, which can be obtained by a large dose of radiation. He then puts his genitals in the microwave.
Meanwhile Cartman and his mother travel to a neighboring town, hoping to appease Cartman's KFC addiction. However, that KFC is also closed, and the construction men there inform Cartman that all of the KFC's have been shut down because of a new law which bans fast food from being sold in low income areas, and since KFC was 'only' in low income areas, in the entire state of Colorado Kentucky Fried Chicken is illegal. Upon hearing this, his head explodes. Soon after, Cartman begins to experience withdrawal symptoms of his addiction and visits a methadone clinic to get over his KFC addiction. They make the attempt by offering him a paper-cup full of a KFC gravy, which he drinks greedily, after a brief protest about the lack of anything else.
The next day Randy wakes up (much to his delight and Sharon's horror) to find that his scrotum and testicles have enlarged to huge proportions. Lab tests at the doctors office confirm that Randy has testicular cancer. While the doctor is intent on giving him treatment for the cancer, Randy only has one thing on his mind, and thus finally gets a prescription for medicinal marijuana. Putting his testicles in a wheelbarrow to move them, he rushes to the pot store to fill the prescription, and proceeds to smoke it in front of Officer Barbrady and his half-brother Jimbo.
On the way back from methadone clinic Cartman finds out on the playground that a boy named Billy Miller has KFC. Cartman goes to see him where he is treated to KFC popcorn chicken, but then Billy charges him $85, which is money that Cartman doesn't have. In order to pay off his debt, Billy suggests that Cartman work as a mule to smuggle KFC into Colorado. Cartman proceeds to take the job, acting like he's purchasing drugs. When he tastes the gravy, he realizes that it's been cut with Boston Market and threatens to shoot the dealer for his attempts at cheating him. Officer Barbrady appears to check on the commotion, but Cartman assures him that everything is fine, despite the KFC behind him, and the cowering drug dealer in front of him.
Meanwhile, as Randy is pushing his wheelbarrow after picking up another day's of weed, it tips over. He is unable to recover, but then, to his drugged out amusement, finds out he can use his testicles like a hoppity-hop, bouncing around town. Later while playing cards with his friends and smoking weed, Randy is shown to be sitting on his balls as a chair and praising the pot, while denying his friends any. He then tells the men that ever since his balls got bigger, women have started to notice. He also claims that women love huge balls (an obvious opposite to the fact that men like large breasts).
Cartman delivers the money and KFC to Billy who tells him that he's rather good at getting KFC in Colorado and will team up with Tommy and go to Kentucky to meet Colonel Sanders, who is alive and well in the "South Park" universe. Upon meeting the Colonel, the plan to smuggle larger quantities of KFC into Colorado begins. Tommy is revealed to be a spy working for Jamie Oliver and is subsequently hung out of a plane by a rope tied round his neck, killing him. Cartman then makes a deal with the Colonel, who warns Cartman not to "fuck him". Upon returning to South Park, Cartman overthrows Billy in running the KFC smuggling operation, by telling Billy's parents that Billy got an 'F' on his Social Studies test.
Every man in South Park is intentionally getting testicular cancer to obtain marijuana and huge testicles. Randy's balls are growing larger and larger as time passes. Sharon notices and wants more sex. Randy tries to get more weed but can no longer fit through the door of the medicinal marijuana store. Randy is informed that it is still illegal to purchase weed outside of an approved store, and subsequently starts a protest with the picket chant "What do we want? Bigger doors! Where do we want them? Weed stores!".
To exaggerate Cartman's addiction to KFC, he starts cutting chicken skins into strips and snorts them. However, Cartman's addiction keeps him from doing proper work for the Colonel, who does not like to be "fucked" with. As such, he sends his goon-squad to take out Cartman and his operation. The cops then arrive at Billy' house to stop the operation, resulting in a massive gun battle, with Billy's mother being killed and Cartman quietly slipping away.
Because of the events of the past few months, weed becomes re-illegalized. Meanwhile the local doctor comes to the belief that KFC apparently has some sort of medicinal property, because of the fact that that men didn't get testicular cancer when it was around. Thus KFC is once again made legal in Colorado, with the new store title of Medicinal Fried Chicken. Randy and the other men all have their cancerous testicles removed and replaced with prostheses that are the same size as normal testicles. Although Randy tolerates the change, Sharon is noticeably disappointed. However, Randy had the extra skin made into a coat and gives it to his delighted wife, while other women becomes jealous of Sharon's new "scrotum coat".