While most games of Impossible Creatures consist of plain battling, the Campaign tells the story behind the game, its characters and the Sigma Technology.
The Campaign is divided into fifteen missions. The overall goal of each is to defeat the opponent(s) presented in each, but there are a plethora of other objectives to complete. A key element of the Campaign is the presence of wild animals, from which the player collects DNA samples for combining. From the first mission, the player is a serious underdog with limited access to structures, animals and resources, but this slowly improves throughout the story as the protagonists acquire more pieces of the Sigma Technology.
Decades before the Campaign takes place, Eric Chanikov and a group of other scientists take part in an experiment involving a weapon known as the Death Ray , on the island of Tunguska. The weapon unleashes a chaotic explosion, causing untold destruction. According to Chanikov, however. the only death was his wife. Somehow as a result of the disaster, the first Sigma Creature Chamber was created. Chanikov's baby son Rex was the only other person exposed to the blast, and survived, but he was imbued with countless attributes from the local environment. For his own protection, Chanikov sent Rex away to North America while he led a life of exile in the little-known Isla Variatas island chain and dedicated his time to further developing the Sigma technology.
Roughly 30 years later in 1937, Rex lives in New York and laments over not knowing his father, and believed he was dead all his life. He recieves a letter from his father, inviting him to the islands to meet him and learn the truth. When he arrives Upton Julius attempts to kidnap him using combined creatures, but Lucy appears in her Lab and saves him just in time. She later explains that she is a colleague of Rex's father, who was kidnapped by Julius for unknown reasons. During their struggle for survival, Rex comes to learn about the wonders of the Sigma Technology and the combined animals it is responsible for, and despite their disagreements, forms a close friendship with Lucy.
Whitey Hooten, Julius's right-hand man, is the first to come after Rex and Lucy. As they eliminate his goons while travelling from island to island, he gloatingly informs them that Rex's father has already been killed. Now driven by a thirst for revenge, Rex uses his knowledge of army strategy to overpower Whitey's creatures and eventually kill him by sinking his ship. They later go through a similar ordeal with Velika La Pette, who harasses them as they continue their travels. Rex and Lucy's creatures soon destroy her base and she is killed when her Gyrocopter crashes into the ocean.
Throughout their fights, Rex and Lucy learn that Upton Julius and his underlings have been abusing the Sigma Technology, going so far as to use the native villagers in their experiments. Rex decides the Technology is too powerful to be allowed to exist, and Lucy is forced to agree when she sees the graves of the many villagers killed in the experiments. They later confront and defeat Otis Ganglion, a deranged veterinarian who conducted the villager experiments, but Lucy is captured by an enormous combined creature sent by Julius. Rex forcibly recruits Ganglion to help him rescue Lucy and defeat Julius.
Through Ganglion, Rex learns the truth about his past, the Tunguska event and the various abilities he has developed since his arrival at the islands. Ganglion also explains that Julius plans to use the Sigma Technology and combined creatures to conquer the world. When they finally arrive on the last of the islands, Julius ambushes him and Ganglion is revealed to be a sneaky backstabber. Julius explains that he wanted Rex to learn about his ability to control combined creatures, and to simply kill him afterwards. Rex is able to turn Julius's own creatures against him, and an intense battle ensues between them, with Ganglion returning to Julius's side. During the fight, Ganglion is killed when a large fan violently hurls him at a wall, and when Julius himself is defeated Rex orders a combined creature to carry him away, which in all likelihood eats him off-screen. Lucy emerges from Julius's Lab unharmed, and she and Rex celebrate that their ordeal is finally over, and go on to live happily ever after.