OBJECTIVE: To review the current state of knowledge on the prevention of sexual transmission of HIV in adolescents and to highlight the existing gaps and priority areas for future research. BACKGROUND: A disproportionate burden of HIV infections falls on adolescents, a developmental stage marked by unique neural, biological, and social transition. Successful interventions are critical to prevent the spread of HIV in this vulnerable population. METHODS: We summarized the current state of research on HIV prevention in adolescents by providing examples of successful interventions and best practices, and highlighting current research gaps. RESULTS: Adolescent interventions fall into 3 main categories: biomedical, behavioral, and structural. The majority of current research has focused on individual behavior change, whereas promising biomedical and structural interventions have been largely understudied in adolescents. Combination prevention interventions may be particularly valuable to this group. CONCLUSIONS: Adolescents have unique needs with respect to HIV prevention, and, thus, interventions should be designed to most effectively reach out to this population with information and services that will be relevant to them.