More than 90% of pediatric HIV infection occurs in sub-Saharan Africa and 75% of these children currently die before their fifth birthday. Most HIV-infected children in Africa rely on district hospitals for HIV treatment, but insufficient attention has been paid to improving HIV/AIDS care at this level. Considerable confusion exists about optimal use of combination antiretroviral treatment, prophylaxis for opportunistic infections and other rational healthcare interventions that can greatly improve the quality of life for these children. A simple and inexpensive infant HIV diagnostic assay and alternative laboratory markers of pediatric HIV disease progression would be highly beneficial. Routine anthropometric and neurodevelopmental assessments could help guide initiation and monitoring of antiretroviral therapy. Even in the absence of antiretroviral therapy, interventions such as immunizations, provision of micronutrients and nutrition counseling, prevention and treatment of opportunistic as well as endemic infections (such as helminths and malaria) can substantially reduce pediatric HIV-related morbidity and mortality. The need for pain relief, palliative care, counseling and emotional support is often underestimated. Surmounting the sense of hopelessness by providing district healthcare workers with training in basic pediatric HIV/AIDS care is an urgent priority.