Comprehensive sexuality education (CSE) is increasingly accepted as the most preferred way of structurally enhancing young peoples’ sexual and reproductive well-being. A historical development can be seen from “conventional,” health-based programs to empowerment-directed, rights-based approaches. Notably the latter have an enormous potential to enable young people to develop accurate and age-appropriate sexual knowledge, attitudes, skills, intentions, and behaviors that contribute to safe, healthy, positive, and gender-equitable relationships. There is ample evidence of program effectiveness, provided basic principles are adhered to in terms of content (e.g., adoption of a broad curriculum, including gender and rights as core elements) and delivery (e.g., learner centeredness). Additional and crucial levers of success are appropriate teacher training, the availability of sexual health services and supplies, and an altogether enabling (school, cultural, and political) context. CSE’s potential extends far beyond individual sexual health outcomes toward, for instance, school social climates and countries’ socioeconomic development. CSE is gaining worldwide political commitment, but a huge gap remains between political frameworks and actual implementation. For CSE to reach scale and its full potential, multicomponent approaches are called for that also address social, ideological, and infrastructural barriers on international, national, and local levels. CSE is a work never done. Current unfinished business comprises, among others, fighting persevering opposition, advancing equitable international cooperation, and realizing ongoing innovation in specific content, delivery, and research-methodological areas.