Objectives: The inclusion of adolescents in HIV prevention clinical research has the potential to improve the current understanding of the safety and efficacy of biomedical prevention technologies in younger populations that are at increasing risk of HIV infection. However, there are significant individual, operational, and community-level barriers to engaging adolescents in clinical prevention trials. Methods: This paper identifies and addresses individual, operational, and community-level barriers to adolescents' participation in HIV biomedical prevention research. Results: Barriers identified and addressed in this paper include: (1) insufficient understanding of clinic prevention research, (2) self-presentation bias, (3) issues surrounding parental consent, (4) access to clinical trials, (5) mistrust of research, and (6) stigma associated with participation in clinical trials. Examples of programs where adolescents have been successfully engaged in prevention research are highlighted and the lessons learned from these programs indicate that establishing collaborations with key stakeholders in the community are essential for conducting biomedical research with vulnerable populations, including adolescents. Conclusions: Given the importance of understanding adolescents' reactions, acceptability, and utilization of new biomedical prevention technologies it is imperative that researchers acknowledge and address these barriers to enhance adolescents participation and retention in HIV biomedical prevention research.