The episode starts with Randy celebrating making 300,000 dollars selling weed. He mocks the family for being critical of his idea, with Shelly snapping back that the farm life was his dream, and not theirs.
At the Family Medical Center, the doctor tries to give Cartman his shot, but, since Cartman is scared, he runs away from the needle, squealing like a pig. At the school, PC Principal speaks to Liane about Cartman's refusal to get shots. Liane explains how this happens multiple times. PC Principal explains that Cartman cannot go to the school if he doesn't get his shot, leading Liane to plead him to give her another try. She suggests a reward and Cartman accepts, before changing his mind when he gets there and running around like a pig again.
Randy parades down Main Street on his float, gloating to the townsfolk about how he made $300,000. He throws beads out to the crowd and sings China, before flashing his dick at people.
At school, the boys discuss how Cartman has been kicked out for not getting his shot. Before Kyle can celebrate, Cartman returns, explaining that, since he is a conscientious objector, he doesn't ever have to get his shot. Stan tries to warn him about how dangerous it is for him to not have his shot, but is interrupted by Cartman sneezing a snot web.
Later, at the PTA meeting, the parents are annoyed that Cartman is not getting his shot, with Liane trying to defend him by reading from a script. When Sheila suggests Liane is a bad mother, Liane yells at her, berating the parents for criticising her without knowing how hard it is to catch Cartman. Stephen offers to help Liane catch Cartman.
That night, when Cartman is asleep, Liane gives a signal to bring the parents inside. The parents sneak in to Cartman's room with the doctor. Before the doctor can give him his shot, Cartman wakes up and starts running around like a pig again, even rubbing himself with grease to stop them from catching him. After he escapes, the parents decide to call up Big Mesquite Murph, an award winning hog wrestler, to help catch Cartman.
Randy shows the family his advert for Tegridy Farms making $300,000. Sharon berates Randy, since they both bought the farm together, and all Randy cares about is the money he made. Shelly then exclaims that she hates marijuana, before Stan does the same.
Liane arrives back at her house, only to find Cartman waiting for her. Cartman yells at her for letting people vaccinate him against his will, since vaccines may have affected Timmy, Jimmy and Token. He then kicks Liane out of her house, explaining he can't live with her anymore. After she leaves, he turns around to find Mesquite waiting for him. He then runs off squealing like a pig, and Mesquite chases after him.
At Skeeter's Bar and Cocktails, the parents confront Mesquite, who explains that he has caught him, but he can't vaccinate him since he keeps running. He then details his idea for a vaccination roundup, where all non-vaccinated kids will be vaccinated.
With nowhere else to turn, Liane goes to Tegridy Farms to buy some weed. There, she speaks to Randy about how vaccinations could be dangerous and how they both try to their best to help their family. Liane manages to persuade Randy to apologise to his partner, while Liane decides to go and save her son.
Randy takes Towelie up on the hill to apologise about being a bad person and losing his integrity. Towelie persuades Randy to stop dealing with China, forcing him to say "Fuck the Chinese Government". After he does, they hug, and Randy tells him Tegridy Farms is now back on trap.
At the CDC Child Immunization challenge, doctors and Big Mesquite Murph chase non-vaccinated kids around a field to catch them and vaccinate them. Cartman is the main event, and manages to run for over 16 minutes. Liane arrives and fights her way through the crowds and the doctors to save her son. In the process, she ends up getting the shot that was meant for Cartman. She then explains to the crowd that whatever happens now will be her choice. Cartman asks if he can get a toy, but Liane refuses to allow him, since he didn't get his shot despite the fact she stopped him from getting shot herself.
Cartman then goes to the Medical Center to get the shot himself. The doctor comes out to explain something had happened to Liane. Cartman goes in to find Liane painting a picture, since the shot made her artistic.
AV Club gave "Shots" a "A" rating saying: "After a shaky premiere, each of the last two episodes have been better than the last, at the season now appears to be on the right track. “SHOTS!!!” was both funny, and surprisingly layered, giving us reason to empathize with every central character."