Background South Africa is likely to be the first country in the world to host an adolescent HIV vaccine trial. Adolescents may be enrolled in late 2007. In the development and review of adolescent HIV vaccine trial protocols there are many complexities to consider, and much work to be done if these important trials are to become a reality. Discussion This article sets out essential requirements for the lawful conduct of adolescent research in South Africa including compliance with consent requirements, (...) child protection laws, and processes for the ethical and regulatory approval of research. Summary This article outlines likely complexities for researchers and research ethics committees, including determining that trial interventions meet current risk standards for child research. Explicit recommendations are made for role-players in other jurisdictions who may also be planning such trials. This article concludes with concrete steps for implementing these important trials in South Africa and other jurisdictions, including planning for consent processes; delineating privacy rights; compiling information necessary for ethics committees to assess risks to child participants; training trial site staff to recognize when disclosures trig mandatory reporting response; networking among relevant ethics commitees; and lobbying the National Regulatory Authority for guidance. (shrink)