Adolescence is a time of dramatic physical, emotional, cognitive, and social change that brings new vulnerabilities. Youth represent half of all new HIV infections in the United States and the rest of the world. The number of newly infected adolescents who acquire the disease behaviorally and the number of perinatally infected children surviving into adolescence have both contributed to this growth. This article reviews the most recent epidemiology of HIV/AIDS in adolescents, gives guidance on clinical practice, including medical and psychosocial care, and examines prevention issues, including counseling and testing, which are needed to make programs effective for youth.