- Three super-powered little girls constantly save the world (or at least the city of Townsville) from monsters, would-be conquerers and a few other gross things.
- The straight-laced Prof. Utonium's attempt to create perfect little girls accidentally includes "Chemical X", resulting in take-charge red-head Blossom, blonde sweety-pie Bubbles and ready-to-fight brunette Buttercup. These flying, super-strong, karate-chopping girls with the occasional heat vision race into action to save the city of Townsville (and, we're told, the world) from all sorts of crimes and creatures.—Ray Schaff -2-
- In the metropolis of Townsville, Professor Utonium blended together sugar, spice and everything nice in the hopes of creating a perfect little girl. However, an accidental dose of Chemical X results in the creation of the Powerpuff Girls. Using their powers to protect Townsville, Blossom, Bubbles and Buttercup come up against a cadre of villains such as Mojo Jojo, Him, Fuzzy Lumpkins, Princess Morbucks, the Amoeba Boys and more.—Blazer346
- The series features a trio of female superheroes, who are sisters to each other. They consist of de facto leader and strategist Blossom (a redhead with pink eyes), the tough tomboy Buttercup (a brunette with green eyes), and the artistic and kind-hearted Bubbles (a blonde with blue eyes).
The trio are raised by their single father Professor Utonium and regularly attend school. As explained in the narration, the girls are not his biological children but the accidental products of an experiment in creating life. Their super-powers are a by-product of the mysterious chemical X which was added to the experiment by mistake.
The trio are tasked with protecting their native city of Townsville against rampaging monsters, local super-villains, generic criminals, and any other threat that comes along. The Mayor of the (a dwarf-like man with a childish personality) regularly phones them at home and at school to assign them with missions.
Other that the Professor and the Mayor, the main supporting characters are secretary Ms. Sara Bellum and teacher Ms. Keane. Bellum is nominally the secretary of the Mayor, but due to his incompetence she is actually the one performing most of his duties and taking decisions. Ms. Keane is the girls' teacher and a former love interest of Professor Utonium. Bellum and Keane jointly serve as mentors of the girls, and they are the closest thing they have to maternal figures.
The rest of the regular cast consists of the recurring villains. The more serious threats among them are the mutant chimpanzee Mojo Jojo (a mad scientist and would-be world conqueror), the manipulative demon HIM (an effeminate version of Satan), the child-aged supervillainess Princess Morbucks (a wealthy classmate of the girls who uses armored battle-suits and technological devices to simulate genuine superpowers),the territorial and perpetually angry hillbilly Fuzzy Lumpkins (a super-strong man with a tendency for berserker-like rampages), the hypnotist and seductress Sedusa (a seductive version of Medusa, who typically relies on emotionally manipulating others), and the teenage delinquents the Gangreen Gang (a collective of local bullies, thugs, and vandals who happen to have green skin).
A late addition to the cast were the Rowdyruff Boys (Brick, Boomer, and Butch), a trio of male clones of the Powerpuff Girls. Created by Mojo Jojo, and (after their initial deaths) resurrected and enhanced by HIM. The trio of young villains apparently shared most of the girls' powers, but they had exaggerated versions of the girls' character flaws, and lacked the girls' intellects and acquired skills.
Many of the dramatic moments of the series depended on the clashing personalities and perspectives of the protagonists, rivalries among the regular villains, and moments of insecurity, self-doubt, or depression felt by various characters.
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