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Purpose School-based sex education plays a vital role in the sexual health and well-being of young people. Little is known, however, about the effectiveness of efforts beyond pregnancy and sexually transmitted disease prevention. The authors conducted a systematic literature review of three decades of research on school-based programs to find evidence for the effectiveness of comprehensive sex education. Methods Researchers searched the ERIC, PsycINFO, and MEDLINE. The research team identified papers meeting the systematic literature review criteria. Of 8,058 relevant articles, 218 met specific review criteria. More than 80% focused solely on pregnancy and disease prevention and were excluded, leaving 39. In the next phase, researchers expanded criteria to studies outside the U.S. to identify evidence reflecting the full range of topic areas. Eighty articles constituted the final review. Results Outcomes include appreciation of sexual diversity, dating and intimate partner violence prevention, development of healthy relationships, prevention of child sex abuse, improved social/emotional learning, and increased media literacy. Substantial evidence supports sex education beginning in elementary school, that is scaffolded and of longer duration, as well as LGBTQ–inclusive education across the school curriculum and a social justice approach to healthy sexuality. Conclusions Review of the literature of the past three decades provides strong support for comprehensive sex education across a range of topics and grade levels. Results provide evidence for the effectiveness of approaches that address a broad definition of sexual health and take positive, affirming, inclusive approaches to human sexuality. Findings strengthen justification for the widespread adoption of the National Sex Education Standards.