According to the journals found in the Pokemon mansion on Cinnabar island, Mewtwo was born of a pregnant Mew, found deep in the jungles of Guyana, whose embryo had been tampered with to alter its DNA. It was held and studied in the mansion where the scientists, including Blaine and Mr. Fuji, performed horrific gene-splicing experiments that made it vicious and extremely powerful. It eventually broke free of the Mansion, destroying it in the process, and fled. It can be encountered in Cerulean Cave, accessible only after a Trainer has proven his or her skill at the Indigo Plateau.
Mewtwo made several appearences in the Anime, like in the games Mewtwo is a clone of Mew. Dr. Fugi trying to make a clone of his dead daughter Amber, is funded by Team Rocket leader Giovanni as long as Fugi makes a clone of Mew. Although the clone of Amber had died, the Mew clone survived.
Over the years, Mewtwo matured and grew confused over its origin and place in the world. After resolving to figure out where it belongs, Mewtwo broke out of its test tube. The Team Rocket scientists were happy that they had succeeded in creating the most powerful Pokémon in the world, but that joy turned to horror once Mewtwo realized that it was just an experiment and unleashed its fury upon them. Despite the efforts of the security systems that attempted to control it, Mewtwo destroyed the laboratory on New Island and all of the scientists in it.
Immediately after, Giovanni found Mewtwo and convinced him to help with Team Rocket's goal of controlling the entire world. Mewtwo's power was focused as well as restrained by a special robotic suit of armor as it performed tasks such as battling for Giovanni in the Viridian Gym and helping Team Rocket capture Pokémon. Mewtwo eventually became tired of being used by Giovanni. It developed a strong hatred for humans and thought that they were weak and selfish beings only interested in power and wealth; it also despised Pokémon who served humans. Mewtwo escaped from Giovanni (destroying Team Rocket headquarters in the process), relocated to its birthplace on New Island and built a castle there. Mewtwo then issued a challenge to several strong Pokémon Trainers, including Ash Ketchum. It used its powers to create a storm that would serve as a test to see who could make it to the island. Only a handful of Trainers managed to brave the storm and arrive, including Ash and his friends. Upon revealing itself, Mewtwo challenged the Trainers with its clone Pokémon, Venusaur, Blastoise, and Charizard, to prove its superiority to human Trainers and the superiority of cloned Pokémon to trained Pokémon. To do this, Mewtwo used a variation of the Poké Balls used by Trainers. Once caught in the Balls, the Pokémon that had been brought to the island were cloned in an upstairs laboratory. However, before Mewtwo could defeat the Trainers and move out into the world, Mew appeared. Mew and Mewtwo fought at length, ceasing only when Ash was caught in their crossfire and turned to stone. After Ash was revived by the tears of the nearby Pokémon, clone and original alike, Mewtwo experienced a change of heart and no longer sought to conquer the world. Mewtwo reasoned that it would be best if no one remembered the events that had transpired, so it erased the memories of all the people and Pokémon and transported them back to the mainland. Mewtwo and Mew left New Island along with all the cloned Pokémon to seek a proper place for themselves to live in peace.
When leaving New island, Mewtwo with the cloned Pokemon head for Johto and arrive at Mount Quena. To remain undetected, Mewtwo made fierce storms to keep humans away but he would try to save humans who are almost killed in his storms.
After a few years, Giovanni found Mewtwo's hiding place via one of Team Rocket's satellites and began a plan to capture it once again. However, this plan was foiled when Mewtwo again met with Ash, who did not remember their previous encounter. Giovanni restrained Mewtwo, but his friends helped it to escape and defeat Giovanni. At the end of the ordeal, Mewtwo erased Giovanni and his soldiers' memories and decided to move throughout the world, searching for the meaning of its life. In the epilogue to Mewtwo Returns and in some TV series opening sequences and movie previews, Mewtwo has been seen wearing a plain brown cape and moving across rooftops at night. Mewtwo also had a passing mention in the special The Mastermind of Mirage Pokémon, when the mirage Mewtwo was created, Mirage Master claimed "This is not the Mewtwo you are familiar with", possibly meaning that he saw Pikachu's memory of Mewtwo.