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.

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.

In 1995, Buena Vista Home Video released a VHS titled The Gene Slamming Begins, which featured the first 3 episodes of Season 1: "Sharkbait", "Sharkbite" and "Sharkstorm" combined into a feature-length format.