College professor Ira Kane is invited by geology teacher/girls' volleyball coach Harry Block to investigate a meteorite that has crashed through the surface rock into a network of underground caverns under the sleepy town of Glen Canyon, Arizona. They collect a sample and find that it consists extraterrestrial, single-celled, nitrogen-based organisms, which evolve rapidly.
A meteor crashes deep into the desert ground near the town of Glen Canyon. The next day, college professor Ira Kan (David Duchovny) and his friend, the geology professor Harry Block (Orlando Jones) investigate the crash site. They meet Wayne Grey (Seann William Scott) a fireman trainee whose car was damaged in the strike, and learn that the meteor fell into a network of underground tunnels. They take a sample, surprised that it oozes out blue liquid. Ira discovers that it harbours extraterrestrial single-celled nitrogen-based organisms that multiply quickly. Impressed by the condensation of millions of years of evolution into a few minutes, the two take the science class to survey the meteor site the next day, but much to their surprise, the cells from the meteor have already evolved into oxygen-converting fungi and alien flatworms that thrive in the atmosphere, later learning that they reproduce through mitosis.
The next day, Ira and Harry find that the army has sealed off the site and begun setting up a base. They meet General Russell Woodman (Ted Levine), and clumsy Dr Allison Reed (Julianne Moore), who both refuse to acknowledge the duo's role in the discovery. Angry, Harry and Ira take Woodman and Reed to court for the right to be part of the research, but Woodman reveals that five years ago, Ira was discharged from the army because of an anthrax vaccine he created which led to terrible physical disorders, and they are barred from the base. Upon reaching their lab, they find Woodman has had it cleaned of all their samples and files. In response, the duo infiltrate the base underground to get another sample, now finding a rainforest teeming with life. Dr Reed notices the intrusion and apprehends them. Their conversation is cut short when an alien insect manages to get inside Harry's body, but a doctor rectally removes it over his extremely vocal protests.
In the morning, Ira and Harry return to the office to find Wayne waiting for them. He has captured a dead unknown amphibian, which killed the owner of a country club. Another strange mammalian creature appears in someone's house but again dies. Ira and Harry believe that the aliens are coming out of the caves and trying to adapt to the oxygen based atmosphere. The trio soon find a cliff overlooking a ground filled with dying winged dinosaur-like creatures, one of which gives birth right before it dies. The young creature has adapted to the oxygen and flies away with a hostage in a mall, so the trio chase it armed with shotguns. Wayne begins singing into a microphone which draws the alien to them and they shoot it down.
The Governor of Arizona (Dan Aykroyd) orders Woodman and the staff for help in containment of the growing problem. Allison explains that in two months, the alien network will engulf the entire United States. Woodman explains his plan to evacuate everyone from five miles of the infected area and bomb the aliens with napalm. However, their attention is diverted by the aliens, which have now evolved into primates and attack them. They manage to fight them off and Allison returns the stolen research material taken from Ira to him, joining his gang on their trip back to the college as the town is evacuated. There, Harry accidentally tosses a match into the specimen petridish, causing a red mass to rapidly grow from the ooze: they realize that heat triggers the rapid evolution of the organisms. Noticing the position of nitrogen on the periodic table, Ira figures that Selenium might be poisonous to the aliens as they are nitrogen-based, just like arsenic is poisonous to carbon-based life-forms. Allison tries to call Woodman to prevent the napalm strike but Woodman refuses the call. Ira's students Deke and Danny (Ethan Suplee and Michael Ray Bower) arrive, and recall that selenium sulfide is the active ingredient in Head & Shoulders shampoo.
Everyone begins to pour the shampoo into a firetruck, whilst Allison and Ira bond. However they are too late as the napalm strike begins, triggering a gargantuan amoeba-like organism to surface from the alien environment. The team decide to press on with the mission and drive under the gigantic organism, finding a rectal hole. They pump the shampoo contents into the hole, causing the organism to explode. Governor Lewis proclaims Ira, Harry, Wayne and Allison as heroes and Wayne is made a firefighter. Ira and Allison skip the festivities to make love in the firetruck. Amusingly, Harry, Ira and Wayne later become spokesmen for Head & Shoulders.
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