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Adolescents and youth aged 15-24 are one of the populations most impacted by the global HIV epidemic with an estimated 50% of new infections occurring in this age group. They are thus one of the prime populations for targeting behavioral and biomedical preventions. However, the dynamics of the HIV epidemic in youth vary widely by geographic region and risk behavior profiles. There are also biological and neurodevelopmental considerations that must be considered in the development, testing, and ultimate dissemination of HIV prevention interventions. These concepts are broadly discussed here.