There have been tremendous advances in the prevention of maternal-to-child transmission of HIV and treatment of HIV-infected children and adolescents. Although multiple classes of anti-HIV drugs are available that can control viral replication and stabilize immune function when used in combination, patients and their providers must also manage complex and frequently toxic regimens. This article updates our original report that summarizes official National Institutes of Health guidelines for the prevention of perinatal HIV infection and the management of pediatric and adolescent HIV infection and provides the most current updates on indications for therapy, recommended first-line therapy, criteria for changing therapy, salvage therapy, novel management strategies, and a comprehensive summary of available antiretroviral agents.