PURPOSE OF REVIEW: Many of the almost 2 million HIV infections that occurred globally in the last year occurred among adolescents and young people, particularly those from East and Southern Africa and within key populations. Global HIV epidemic control will require that new infections among these youth populations be curtailed. This review examines the most effective prevention approaches to reach these adolescent populations in the next 5 years. RECENT FINDINGS: Adolescents are in transition and are developmentally unique. They have specific needs and challenges, which if not addressed will result in less than successful interventions. Tailored, layered, combination prevention packages that take into account specific adolescent needs and involve biomedical, behavioural and structural components are recommended. These packages should be designed for and with the meaningful input of adolescents, and involve their peers in their implementation and execution. Where possible, age-appropriate health and social interventions that go beyond HIV should be bundled and offered in a variety of community-based venues that are already acceptable to and frequented by adolescents. SUMMARY: It is urgent that we reach adolescents globally with the most effective HIV prevention approaches. HIV prevention investment in this population has immediate and longer-term benefits.