Clinical manifestations in children living with HIV/ AIDS differ from those in adults due to poorly developed immunity that allows greater dissemination throughout various organs. In developing countries, HIV-infected children have an increased frequency of malnutrition and common childhood infections such as ear infections, pneumonias, gastroenteritis and tuberculosis. The symptoms common to many treatable conditions, such as recurrent fever, diarrhea and generalized dermatitis, tend to be more persistent and severe and often do not respond as well to treatment. The use of Anti Retroviral Therapy (ART) has greatly increased the long term survival of perinatally infected children so that AIDS is becoming a manageable chronic illness. As the immunity is maintained, the incidence of infectious complications is declining while noninfectious complications of HIV are more frequently encountered. Regular clinical monitoring with immunological and virological monitoring and the introduction of genotypic and phenotypic resistance testing where resources are available have allowed for dramatically better clinical outcomes. However, these growing children are left facing the challenges of lifelong adherence with complex treatment regimens, compounded by complex psycho-social, mental and neuro-cognitive issues. These unique challenges must be recognized and understood in order to provide appropriate medical management.