Malcolm Medusa III and Clammando are back and have been hunting Florida panthers in the Everglades as part of a plot to develop a chemical waste incinerator there. After Moby Lick has been caught by Malcolm when trying to rescue them, the President enlists the Street Sharks to investigate where the trace the Florida panthers and Moby Lick to a nearby island where Malcolm has used a petrifying laser to petrify Moby Lick, the Florida panthers, and other wildlife in the Everglades. Now Malcolm plans to have the Street Sharks provide a hunting challenge for him.

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.

Dr. Paradigm is visited by his future counterpart in his Time-Slammer where they work on a plan to develop a mechanism to alter the world's genetic code by New Year's Eve. The Street Sharks are tipped off about the disturbance in the time-space continuum by Dr. Bolton and work with Mantaman and El Swordo to thwart the two Dr. Paradigms and the future Dr. Paradigm's Mechosharks.

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.

Maximilian Greco is back and has established a casino called the Golden Greco while making its surrounding areas as part of Fission City's casino district. Dr. Paradigm sends Repteel and Shrimp Louie to raid the Golden Greco and steal all the money there. Yet Repteel and Shrimp Louie continue to rob other casinos causing Dr. Paradigm to send Killamari after them up to the point where the Seaviants are enlisted by Maximilian Greco to take over the casino district.

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.

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.

Dr. Piranoid has Killamari and Tentakill capture Mantaman's younger brother Ryan so that he can get Mantaman to hijack two jets with one of them carrying the Latonian president and the other one carrying the Coachnian president where both of them are to be meeting with President Horne the next day. While Mantaman does the hijacking, Bends and the Street Sharks work on playing along while finding out where Dr. Piranoid is keeping Ryan. During that time, Dr. Piranoid has created the Genesis Satellite to end the world's woes by detonating it so that the world can be turned into mutated creatures.

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.

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.

An aged crime boss named Maximilian Greco discovers Ripster and Streex fighting Killamari and Repteel at a nearby zoo as part of Dr. Paradigm's plot to obtain animal specimens for his Genetic Engineering Chamber. Upon tracing Killamari and Repteel back to Dr. Paradigm, Maximilian Greco blackmails him into enhancing him with the strength of a rhinoceros and the longevity of a desert tortoise. Maximilian also has Dr. Paradigm have his chihuahuas Zeus and Apollo enhanced to fight the Street Sharks.

At the time when El Swordo is entertaining the USS Liberty, a four-headed sea monster (where some navy officers have compared it to Scylla) has been attacking ships and submarines at sea. To prevent an international incident, President Horne enlists the Street Sharks to look into this. The Street Sharks work with El Swordo in order to keep the four-headed sea monster from attacking ships.

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.

At the time when Jab is going to compete in the Cross-Country Grand Prix, Dr. Paradigm creates the Gene-Slam Bomb and places it in the Turbo Jab vehicle so that it would detonate at the Cross-Country Grand Prix if Jab does not have his car running at 65 MPH. The plot thickens when the International Trade Conference that is signing the Big Trade Agreement is threatened by Dr. Paradigm's Gene-Washing Bomb within an ice sculpture of two dolphins.

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 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.

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.

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.)