Cady Heron je odrasla v afriški divjini, zato verjame, da ve vse o preživetju najmočnejših. Toda ko jo pri petnajstih starša prvič pošljeta v pravo ameriško srednjo šolo, Cady spozna, da do sedaj ni imela pojma o boju za preživetje. V novem okolju kmalu postane žrtev psiholoških igric, s katerimi se kratkočasijo tri najbolj priljubljena dekleta na šoli. Ko jo povabijo medse, Cady sicer okleva, vendar jo prijatelji prepričajo, da se pridruži trojici in se dokoplje do njihovih najglobljih skrivnosti. Toda načrt se kmalu ponesreči, saj Cady zagreši usodno napako in tako postane njihova tarča.
Her parents being zoologists, homeschooled Cady Heron lived in Africa for 15 years. Attending a Chicago public high school for the first time, she starts out by befriending the "best people you will meet", Janis, a supposedly lesbian girl; and Damian, a boy "too gay to function". Cady is warned to avoid the "worst people you will ever meet", the Plastics--a clique comprised of three girls: Gretchen Wieners, a girl who's rich because her father invented toaster strudel; Karen Smith, the "dumbest girl you will ever meet"; and Regina George, the unofficial leader and the meanest one. She becomes a hit with the Plastics and eventually assimilates into the clique, only for Janis to ask her sabotage them. After conflicts involving Regina's ex-boyfriend, Aaron Samuels, Cady later becomes tied between being part of them or sabotaging them. Whilst eventually becoming one, she sabotages them. She tricks Regina into eating fattening candy bars that she claims will make her skinny, tries to break her and Samuel up, and tries to turn her fellow Plastics, Karen and Gretchen against her. Will she be caught? Will she become too Plastic and become the fourth Plastic?