High school students Janis Sarkisian and Damian Hubbard relate the story of Cady Heron ("A Cautionary Tale"). Cady and her parents have moved from Africa to start a new life in the outside world ("It Roars"), with Cady entered in public school. She is very excited to make new friends but no one seems to like her ("It Roars" (Reprise)). Janis and Damian discover Cady and they help her find her “group” and she ends up with them, aka "the greatest people you will ever meet" ("Where Do You Belong"). Janis and Damian tell her about the Plastics, the most popular girls in school: Regina George who is the Queen Bee, Gretchen Wieners who knows everything about everyone, and Karen Smith who is the dumb blonde. Just as Cady walks to eat lunch with Janis and Damian, Regina and her fellow Plastics decide that she will eat lunch with them for the rest of the week ("Meet the Plastics").
In calculus class, Cady meets the dreamy Aaron Samuels and she immediately falls for him ("Stupid with Love"). Janis tells Cady to follow through with the Plastics and tell her everything they say. Cady thinks Regina is a nice girl but Janis tells her not to fall for it ("Apex Predator"). The Plastics and Cady all go to the mall, then go to hang out at Regina's house. There, they meet her "cool mom," and Gretchen confides in Cady that, because of the state of her friendship with Regina, she has lost all self-confidence ("What's Wrong With Me?").
The next day in math class, Aaron discusses his previous relationship with Regina, and how she made him feel like not-himself, so he has sworn off dating. Meanwhile, Cady believes that if she acts stupid, Aaron will help her with her work, and therefore talk to her more ("Stupid With Love" (Reprise)).
Later, Karen explains that in high school, Halloween revolves around looking sexy, and how no matter what you are dressed as (even if you are dressed as corn or Rosa Parks), the costume must be hot ("Sexy"). Later, at Aaron's Halloween party, Regina discovers Cady's crush on Aaron. Spitefully, Regina decides to flirt with him until he agrees to get back together with her ("Someone Gets Hurt").
Furious, Cady goes to Janis and Damian for advice. They decide that they will work together to get revenge on Regina, giving her Kälteen Bars to help her gain weight (though she thinks she is losing weight). They also convince Gretchen that Regina is mad at her by sending a fake Candy Cane Gram to Cady from "Regina" saying that they are now best friends - causing her to reveal Regina's secret hook-ups with Shane Oman in the North Shore Lion's mascot costume, among other vengeful acts ("Revenge Party"). After failing their "Rockin' Around the Pole" dance at the school talent show, people start noticing Regina's weight gain. Later, when Regina breaks one of the Plastics' "rules", Cady stands up to her, banning her from sitting at their table. Everyone is relieved to be freed from Regina's rule ("Fearless"). Cady tries to apologize to Regina for kicking her from the lunch table, but Regina insinuates that her reign is far from over ("Someone Gets Hurt (Reprise)").
After winter break at North Shore High School, Cady is seen as having undergone a complete makeover befitting of her new "Queen Bee" status ("A Cautionary Tale" (Reprise)). Damian, Janis, and the other girls of North Shore High try to hamper Cady's ever-growing social obsessions, and to stop acting dumb for Aaron by telling her about their own negative past experiences with obsessive behavior ("Stop"). Gretchen starts to notice similarities between her friendship with Regina, and her friendship with new Queen Bee Cady, while Regina's mother wonders why her daughter won't confide in her ("What's Wrong With Me (reprise)").
Cady throws a house party in an attempt to get Aaron to her house - despite telling her parents that Janis had an art show, so she couldn't go on their family trip (when, in fact, Janis did have an art show, and Cady just did not choose to go). She becomes drunker and drunker as the party goes on and gets crazier ("Whose House is This?"). When Aaron shows up to a drunk Cady's party, they sneak off to her bedroom. There, Aaron explains that he really liked who Cady was before she became Plastic, whereas Cady tries, unsuccessfully, to convince him that since she has more now, she is, therefore, better ("More is Better"). After the party, Janis and Damian show up at Cady's house, angry she missed Janis's art show. They tell Cady that she betrayed their trust, and has gone full Plastic ("Someone Gets Hurt" (Reprise 2)).
When Regina discovers that she was not invited to this party and that the Kälteen Bars are what made her gain weight, she decides to get revenge by releasing the Burn Book - a book full of insults to each and every girl (as well as Aaron and Damian) in the school - later adding "Regina is a Fugly Cow" to the book in order to take the blame off of herself ("World Burn"). At a required assembly about the Burn Book, Ms. Norbury tries to bring the girls together. In that time, Janis explains her philosophy of "I'd rather be me than be with you" to the school, referencing her failed friendship with both Cady and Regina. Janis and Regina had been best friends until, at an all-girls' sleepover, Regina refused to invite Janis because Regina was convinced Janis was a lesbian ("I'd Rather Be Me").
Cady decides to take the blame for the Burn Book in order to end the drama and gets suspended. As she is leaving, she sees Regina and tries to apologize, but Regina is so distracted that she walks in front of a bus and gets hit. Luckily, however, she survives. Cady slowly starts apologizing to everybody in the school for her behavior as Queen Bee ("Fearless" (Reprise)).
To raise her math grade after failing for Aaron, Mrs. Norbury has Cady join the Mathletes in the state championships. After being up against the only other girl in the competition and winning, the team wins, and Cady feels redeemed ("Do This Thing"). She then sneaks into Spring Fling with Aaron's help, after kissing him. There, she sees Regina, and they have a heart to heart conversation and create a truce.
Cady is elected as Spring Fling Queen but notices how easily the plastic crown can break. She takes the crown, breaks it into many pieces, and gives a piece to each girl at Spring Fling while complimenting each one - telling them they are all "real, and rare." She apologizes to Janis and Damian, and they move forward as friends once again ("I See Stars").
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