Perinatal HIV infection in the US continues to evolve from a fatal pediatric illness to a chronic medical condition of childhood and adolescence. Although navigating this period is influenced by multi-leveled deprivations commonly experienced by low-income minority families, HIV alters the timing and experience of developmental milestones for many adolescents with perinatal HIV. This selective review of the growing developmental psychopathology literature and the authors' clinical work at a pediatric HIV program in Harlem, NY provide an overview of how developmental psychopathology offers an integrative framework that elucidates how autonomy, peer relationships, and self-concept evolve among 13-21 year old adolescents. This paper highlights the importance of considering influences of both perinatal HIV and the culture of poverty on adolescent development, and of adopting multilevel interventions and research to address how interactions among biologic, environmental, and HIV-related stressors (serostatus disclosure, medical treatment adherence, illness stigma) influence the development of adolescents with perinatal HIV.