HIV-infected adolescents represent a unique, yet diverse, population requiring specialized medical and psychosocial HIV care. Perinatally infected and behaviorally infected adolescents often have differing therapeutic needs, but may share common difficulties, including medication nonadherence, high-risk sexual behavior, psychosocial stressors, and concomitant psychiatric disorders. Addressing these needs within a culturally sensitive framework and in the context of a population-specific approach to treatment is paramount to optimizing care. Harm reduction for this group to maximize their health and limit HIV transmission to others is also critical with respect to the rising incidence of newly diagnosed HIV-positive adolescents. Implementing a formal, multidisciplinary program that involves individual youths and their families for improved transition to adult HIV care will afford such adolescents a better chance for a healthy adulthood.