The story unfolds in a future era, where a rampant canine flu prompts the Mayor (voiced by Kunichi Nomura) to enact a Dog Exile Act, banishing all dogs from the city to "Trash Island" and leaving them to fend for themselves. The Mayor's own guard dog, Spots (voiced by Liev Schreiber), is the first to be sent away. Thus, dogs once pampered in comfortable homes are reduced to strays scavenging for food in heaps of garbage. Chief (voiced by Bryan Cranston), Rex (voiced by Edward Norton), Boss (voiced by Bill Murray), Duke (voiced by Jeff Goldblum), and King (voiced by Bob Balaban) are five stray dogs on the island who usually stick together. One day, the Mayor's adopted son, Atari (voiced by Koyu Rankin), suddenly lands a plane on the island, determined to find his lifelong friend, Spots.