A university professor named Dr. Robert Bolton and his partner Dr. Luther Paradigm create 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 the resulting battle causes Paradigm to be combined with piranha DNA (for which he is often nicknamed "Dr. Piranoid" by other characters). While the Street Sharks are known to enjoy eating hot dogs, hamburgers, and shakes, they have shown a disdain for pizza when they shoot down that suggestion to Bends and Lena Mack.
In subsequent episodes, Dr. Paradigm creates a variety of mutant animals to destroy the Street Sharks while attempting to persuade the inhabitants of their native metropolis of Fission City to imprison them. Of these mutant animals, a few sided with the Sharks themselves: namely Rox, Moby Lick, Mantaman, and El Swordo.
The final few episodes introduced the Dino Vengers: a group of extraterrestrial dinosaurs allied with the Street Sharks against their own rivals in the Raptor Gang. When Dr. Paradigm wanted to get a sample of the Raptors' DNA to improve himself, they trick him by giving him iguana DNA which transforms him into "Dr. Iguanazoid" leading to him working with the Raptors where they will reward him by correcting the DNA mistake they gave him. In the end, Paradigm is captured and imprisoned while the Raptor Gang leaves Earth.
The Dino Vengers later had their own series called Extreme Dinosaurs where they and the Raptors had different backgrounds.
