Richard Tarbell, the sheriff of a small island town called North Port, wakes up one morning to find several cockroaches in his house. He goes to the airport to pick up Elizabeth Johnson, the daughter of town mayor Elias Johnson and a former girlfriend of Richard, who is returning from a four-year absence in time for her father's birthday. Strange occurrences happen around the town—the bindings of every book in the local library have been damaged, and several dogs have been reduced to bloody carcasses.
Dr. Morgan Hubbard arrives in town to investigate the dog deaths. She places a trap containing a live cat as bait; a number of cockroaches are lured to the trap, wherein they attack the cat. While Hubbard studies the insects, Elizabeth visits the local diner, owned by Richard's current girlfriend, Lillian. Homer, the local pest control agent, attempts to exterminate some cockroaches inside the establishment.
Hubbard notes that the cockroaches can reproduce asexually, and her hand is wounded by cockroach bites as she studies them. She sprays the insects with rotenone, but is only able to kill them using a dosage also lethal to humans. Elias suggests they evacuate the island, but Hubbard persuades him not to. Meanwhile, Richard shows a number of small objects found on a dog carcass to Homer, who identifies them as Periplaneta droppings. Richard's secretary Millie informs him that Hubbard worked in genetics at MIT, and that she performed illegal experiments.
Elizabeth ventures into a cave and discovers equipment belonging to INTEC, a corporation with whom Elias made a deal to develop the island. After being chased from the cave by cockroaches, she and Richard confront Elias and Hubbard. When Elias demands that Richard cease his investigations, Richard resigns from his position as sheriff. At the diner, an employee named Church is killed by cockroaches. Elsewhere, Homer finds his friend Jake dead, with cockroaches crawling on his corpse. At Richard's house, Richard and Elizabeth find the bathroom toilet swarming with cockroaches. The local librarian, Mrs. Pennington, is attacked in bed by the insects.
Elias calls Mr. Hauser, a representative at INTEC, and demands that they take action against the cockroaches, or else he will reveal information to the national media. Hauser agrees to spray the island with lethal insecticide at 5 a.m. Elias adds that if residents are unable to evacuate, they will turn on the local lighthouse beam; if the beam is on, they are not to spray the island. Hubbard notices that cockroach egg capsules which survived the rotenone have hatched, and are now immune to the chemical.
Richard finds both Millie and Lillian dead. Homer, in an attempt to kill cockroaches, accidentally sets a flammable insecticide aflame, causing his own house to explode. Richard and Homer confront Hubbard, who reveals that INTEC created a species of cockroach designed to eat other cockroaches and then die after one generation; however, the engineered cockroaches did not die after one generation. In order to prevent INTEC from spraying the island and thereby making the eggs located in a nest in the cave immune to the spray, Richard and Homer set out to turn the lighthouse beam on.
Elias and Elizabeth are attacked by cockroaches in Elias's home. Richard, Homer, and Hubbard find a cat-cockroach hybrid that attacks Richard and is crushed by Homer. Elias is killed by the cockroaches and returns as a human-cockroach hybrid, which Elizabeth kills using a shotgun. Elizabeth and Hubbard drive to the cave and find the insects' nest. Richard follows them there, while Homer heads to the lighthouse. In the cave, Hubbard is killed by a queen cockroach-human hybrid. Elizabeth and Richard detonate an explosive inside the cave, and Homer turns on the lighthouse beam, stopping INTEC from spraying the island.
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