Adolescents continue to be at high risk for HIV infection, with young men who have sex with men and youth with drug abuse and/or mental health problems at particularly high risk. Multiple factors may interact to confer risk for these youth. Engaging vulnerable youth in HIV prevention research can present unique challenges in the areas of enrollment, retention, and trial adherence. Examples of successful engagement with vulnerable youth offer encouraging evidence for the feasibility of including these youth in clinical trials. Ethical challenges must be taken into consideration before embarking on biomedical HIV prevention studies with vulnerable youth, especially in the global context. Given the many individual and contextual factors that contribute to their high-risk status, it is essential that vulnerable youth populations be included in HIV prevention clinical research studies. © 2010 by Lippincott Williams & Wilkins.