The premise of the story states that a university professor named Dr. Robert Bolton and his partner Dr. Luther Paradigm created a machine known as the "gene-slammer" which is capable of changing aquatic animals into anthropomorphic hybrids by combining their DNA. In his attempt to prevent Paradigm from using this machine for personal power, Bolton is transformed into an unseen monstrosity, but escapes. Later, Paradigm gives Bolton's four sons John, Bobby, Coop, and Clint the likeness of four different sharks. When Dr. Paradigm captures their friend Bends, the resulting "Street Sharks" rescue him and combine Paradigm with piranha DNA (for which he is often nicknamed "Dr. Piranoid" by other characters). In subsequent episodes, Dr. Paradigm creates a variety of monsters to destroy the Street Sharks while attempting to persuade the inhabitants of their native metropolis of Fission City to imprison them. Of these monsters, a few sided with the Sharks themselves: namely Rox, Moby Lick, Mantaman, and El Swordo.