The past two decades have witnessed dramatic reductions in HIV-related morbidity and mortality following the introduction of combination antiretroviral therapy (cART) for infants and children. Improved therapeutic outcomes have changed the face of the HIV epidemic and with it the needs of patients and families. Consequently, many perinatally- and behaviorally-infected adolescents are now transitioning to adult care. What follows is a brief review and commentary concerning original research, reviews, and clinical guidelines describing challenges and best practices in facilitating care transitions for HIV-infected youth to adult care. Over 25,000 HIV-infected US youth aged 13-24 years will require transition to adult care within the next decade. Transition planning must address issues of cognitive development and mental health, medication adherence, sexuality, reproductive, and gender identity, socioeconomic and health insurance status, stigma and disclosure, disrupted relationships with pediatric care providers, and communication. Clinical experience with HIV and other chronic illnesses supports a multidisciplinary, developmentally-sensitive approach to meeting the challenges inherent in care transition that begins early and is monitored with regular evaluation and revision. Specific clinical recommendations have been made by the U.S. Department of Health and Human Services and the New York State Department of Health AIDS Institute.