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Rowf (a Labrador-mix) and Snitter (a smooth fox terrier) are two of many dogs used for experimental purposes at an animal research facility in the Lake District of north-western England. Snitter has had his brain experimented upon while Rowf has been drowned and resuscitated repeatedly. One evening, Snitter squeezes under the netting of his cage and into Rowf's, where they discover his cage is unlatched. They explore the facility in order to escape until they sneak into the incinerator, where they are nearly killed before finally escaping.
The lives of one highly educated red-tailed hawk named Orville and Kate, a 12-year-old girl, intersect one day on South Dakota ranchland. Orville has a slight vision problem due to faulty DNA, and Kate needs a friend. When Orville crash lands into the side of the Flannery’s home, Kate and her parents rescue him and take him to the local vet for treatment. With Orville’s broken leg nearly healed, he and Kate go fishing. Orville flies back, carrying the fishing pole in his talons, as part of his physical therapy, while Kate walks alone across the vast prairie. Only she does not arrive. Her parents gone for the Labor Day Weekend, leaving a slightly addled grandmother at home, now creates a desperate situation for Kate. Orville and his schoolmates, the county sheriff’s department, and a police dog named Deputy Grace must combine forces to find Kate before it’s too late.