In the Western Cape province of South Africa, a prevention of mother-to-child-transmission (PMTCT) intervention programme, based on short-course nevirapine, achieved universal coverage in 2003. Despite this programme, an estimated 1400–1650 HIV-infected children were born in the province in that year. These crude estimates suggest that there are many children in the province who need medical care. Several strategies could collectively reduce the size of the paediatric epidemic and improve the outcome of HIV-infected children in the region, including intensification of the existing PMTCT programme and provision of antiretroviral therapy (ART) for children with moderate or severe disease. Progress towards implementing these interventions is discussed. Future challenges include understanding the factors that favour long-term survival of children on highly active antiretroviral therapy in resource-limited settings, identifying appropriate treatment for the metabolic complications of ART, and the provision of adolescent services for long-term survivors. Developments over the next few years will determine whether these challenges can be met.