The search for a safe effective HIV vaccine has been a centerpiece of HIV research for almost 2 decades. More than 60 clinical HIV vaccine trials have been conducted to date. Several promising candidate HIV vaccines are in advanced clinical development. To date, however, no trial has included adolescents, one of the most important target groups for any preventive HIV vaccine. To license a vaccine for use in this age group, efficacy data or, at a minimum, bridging safety and immunogenicity data in this population are needed. To accomplish this, several critical issues and special challenges in the development and implementation of HIV vaccine trials in adolescents must be addressed, including regulatory considerations, potential differentials in safety and immunogenicity, alternative trial design strategies, recruitment and retention challenges, community involvement models, and approaches to informed consent/assent. This article examines these issues and proposes specific next steps to facilitate the routine inclusion of this high-priority population in preventive HIV vaccine trials as early and seamlessly as possible. © 2008 Lippincott Williams & Wilkins, Inc.