While the Street Sharks are going out for burgers, Dr. Paradigm transforms a squid he has acquired into Killamari who becomes the latest member of the Seaviates. The Sharks have to stop them from breaking into the Bolton home and stealing important genetic research data that their father left behind.

Dr. Robert Bolton had invented a gene-slamming device for peaceful uses until his colleague Dr. Luther Paradigm uses it for his evil purposes. When Dr. Bolton tries to intervene, he ends up gene-slammed into an unseen inhuman creature during the struggle and escapes. While in search of their father, John, Clint, Robert, and Coop are mutated into humanoid sharks by the evil Dr. Paradigm. While adapting to their new looks, the four brothers must avoid being seen.

When a musician called Melvin Kresnik accidentally digests contaminated popcorn and water that was tainted with a gene-slamming chemical, he becomes a mako shark later known as Rox and befriends the Street Sharks. Together, they have to save the concert in town and its attendants from being mutated into more sea creatures through the same way that Rox was mutated.

With the help of a mind-control serum, Dr. Paradigm turns Jets Taylor into a killer whale mutant named Moby Lick to be his latest Seaviate.

The citizens of Fission City hear an announcement from Dr. Paradigm that he has invented a vaccine against the gene-slamming formula.

Rox is back in town for the Fission City Music Awards and plans to play the evidence that would expose Dr. Paradigm's gene-slamming activities.

The Street Sharks are on a runaway from the police along with their friends Bends and Dr. Lena. The Street Sharks must find a new place to live in and be safe from society.

When Streex has been captured by Dr. Paradigm, the rest of the Street Sharks alongside Moby Lick take to the roads to rescue him.

Ripster, Jab, Streex, and Slammu must protect their reputations and change the way they are being viewed in Fission City. They must fight Dr. Piranoid as well as finding their father once and for all.

When his hotel had been previously destroyed by the Street Sharks and no family members to live with, Mr. Cunneyworth allows Dr. Paradigm to gene-slam him with the DNA of an electric eel and a moray eel which transforms him into Repteel. While Repteel is ordered by Dr. Paradigm to steal an advanced supercomputer part for his robotic machine, the Street Sharks take a cruise around the city to find the doctor's new Seaviate's location and put a stop to their evil plans.

The Street Sharks discover an underground civilization of mutant crocodiles that happen to know Dr. Bolton after he cured them of their damaged genes. Meanwhile, Dr. Paradigm rebuilds Sharkbot and captures one of the mutant crocodiles.

The Street Sharks are framed and brought out of hiding by Sharkbot, the robotic machine built by Dr. Paradigm in the last episode. The Street Sharks must once again defend their reputations and take on Sharkbot.

Dr. Paradigm captures Big Slammu to control his mind and the Street Sharks must break into Dr. Paradigm's hideout to save their brother.

Jab and Streex are sent back in time in two different eras by Dr. Paradigm's time machine called the Time Slammer. Back in the present, Slammu, Ripster, and Bends have to deal with Dr. Piranoid's Seaviates who are now joined by Shrimp Louie. With the help of some Atlanteans, Jab is able to travel in time to save his brother Streex.

Dr. Paradigm creates Tentakill as part of his time-traveling plot to have Killamari go back to the medieval times and kill the Street Shark's ancestor Sir Thomas Bolton. Ripster and Big Slammu hijack Dr. Paradigm's Time Slammer to prevent Sir Thomas Bolton from being killed.

The Street Sharks are sent to a future where Dr. Piranoid controls everything. They meet up with Bends' great-great-grandson General Bendsini and join the rebel forces.

The Street Sharks go to Washington D.C. to save President David Horne from being "gene washed" by Dr. Piranoid as part of his plot to control President Horne after he had successfully gene-washed Vice-President Russell.

The Street Sharks and Bends travel to the country of Chernosium to help a child named Ilya (who had sent them a fan letter), rescue his father President Andre Knezevic, and overthrow a dictator named Ekerson Nozum.

After extracting alien DNA from a sample found on an asteroid, Dr. Piranoid tries to gene-slam the entire planet with this alien DNA mixed with manta ray DNA. The Street Sharks are sent up to space, per the president's request and help, to not only stop Dr. Piranoid's gene slamming plan, but also defeat the alien monster that was released from the sample. They end up getting help from Dr. Terrence Morton (who ends up becoming Mantaman in order to help fight the alien.)

Lena's brother Malik is among those who have been taking strength-enhancing pills. Ripster goes undercover to trace the source of the pills and discovers that a drug dealer named Jackal has been distributing the pills in order to get some recruits to help rob a bank.

The Street Sharks have suddenly become human again due to a formula made by Dr. Piranoid as part of a plot to keep the Street Sharks human permanently.

While investigating the killer whale attacks, the Street Sharks and Moby Lick trace the attacks to Malcolm Medusa III's marine animal sanctuary called Medusa Cove which is being covered up by holograms to hide the pollution and trapped whales. They discover that businessman Malcolm Medusa III and Clammando have been using holograms to keep the town from knowing what is really happening.

Mantaman returns to Earth to help the Street Sharks fight the energy-draining alien (which survived the space station's destruction in "Space Sharks") before it starts draining Earth's electricity.

The Stromboli Circus is in town where El Swordo and his swordfish Spike are the main attraction. Spike is soon targeted by Dr. Piranoid so that he can mutate and control it with the Chromifier Ray so that he can gain control of a satellite and control every head of state in the universe.

Fission City has suffered a blackout as Dr. Paradigm unveils the Wolverinepedes (a wolverine/centipede hybrid) which will be a solution to Fission City's toxic waste problems. The Street Sharks are contacted by Paxel of the G.E.C.O.s (short for Genetic Engineered Cave Organism) on behalf of Robert Bolton where they learn that toxic waste is leaking into their underground home beneath the garbage dump. The Street Sharks discover that the Wolverinepedes are a cover for Dr. Piranoid's illegal toxic waste-dumping property where the Wolverinepedes have been getting bigger from the consumption of toxic waste.