Frank Detorre (Bill Murray) is an unkempt, slovenly zookeeper at the Sucat Memorial Zoo in Rhode Island. Depressed by the loss of his wife years earlier, he copes by unhealthy eating and ignoring basic hygiene, to the annoyance of his young daughter Shane (Elena Franklin).
Osmosis "Ozzy" Jones (Chris Rock) is a rebellious officer of the Frank PD, who was demoted to patrol duty in the mouth after an incident where he induced Frank to vomit against orders (after being the only one to see a salmonella germ on an oyster Frank consumed), resulting in Frank being fired from his previous job at a pea soup factory and banned from visiting Shane's school due to a restraining order filed by her science teacher, Mrs. Boyd (Molly Shannon), who'd he'd accidentally vomited on in the process.
Facing a serious challenge to his re-election prospects, Mayor Phlegmming (William Shatner) doubles down on his junk-food policies, ignoring their effect on Frank's health. This causes Frank to eat a boiled egg covered in filth, allowing Thrax (Laurence Fishburne), a deadly virus, to enter the throat. Unwilling to admit responsibility, Phlegmming instructs Frank to take a cold suppressant though brain signals. The suppressant, Drixenol "Drix" Koldreliff (David Hyde Pierce), proceeds to disinfect the throat, covering up any evidence of Thrax's arrival. To his displeasure, Ozzy is subsequently assigned to assist Drix in his investigation. Meanwhile, Thrax assumes leadership of a gang of sweat germs and launches an attack on the mucus dam in Frank's nose, nearly killing Drix before Ozzy rescues him. The two pay a visit to one of Ozzy's informants, who reveals Thrax's plan to pose as a mere cold virus as a cover for killing Frank with a high fever in order to become the next big virus in the medical records. Based on his information, Ozzy goes undercover at a nightclub intending to infiltrate Thrax's gang, only to be discovered and forced to call in Drix, who manages to destroy the club and kill most of Thrax's henchmen with a grenade. The explosion pops a zit on Frank's forehead during a meeting with Mrs. Boyd, ruining any chance for him to apologize. In response, Phlegmming closes the investigation, fires Ozzy, and orders Drix to leave the city.
Having survived the assault, Thrax eliminates his remaining henchmen and breaks into the hypothalamus gland (the portion of the brain that controls body temperature), where he steals a DNA bead. He then abducts the Mayor's secretary, Leah Estrogen (Brandy Norwood), and flees to the mouth to escape. His actions disable the body's ability to regulate temperature, causing the city to break out in flames and panic. As Frank is taken to the hospital in a fever coma, Ozzy and Drix reconcile and proceed to rescue Leah. They succeed, but Thrax is able to exit the mouth using pollen as a distraction. Ozzy pursues him to the surface of Shane's left eye, and as they fight they both land on Shane's left false eyelash when she blinks. As Thrax has Ozzy pinned down, he threatens to break his own record by killing Shane but gets stuck in the false eyelash; Ozzy escapes at the last minute before the eyelash slides off and lands in a vessel of alcohol, dissolving Thrax to death.
As Frank's temperature goes over 108 degrees, his heart begins to shut down. Riding one of Shane's tears, Ozzy reenters his body and replaces the missing chromosome, reviving him just in time. Having narrowly cheated death, Frank commits himself to living a healthier lifestyle for himself and Shane, while Ozzy is re-instated to the force with Drix as his new partner, and begins a relationship with Leah. Phlegmming later loses his position as mayor, is reduced to a custodian in the bowels, and later ejects himself by accidently pushing a button that triggers Frank's flatulence.
What does Ozzy do after he reenters Shane's body ?
Replaces the missing chromosome