Currently, <10% of all HIV-infected children who need anti-retroviral therapy in sub-Saharan Africa are actually receiving therapy. Many constraints prevent these children from gaining access to appropriate care, including the magnitude of the paediatric epidemic, competing interests of adult care, health system inadequacies, technical challenges and patient-related factors. These issues form the basis of this paper which discusses the practical challenges of extending optimal care to all deserving children. Besides the need for major human, infrastructural, technical and logistic investments to overcome existing constraints, more clinical research is required before treatment guidelines can be refined in resource-constrained settings. In this regard, the paper lists some important research questions that should be addressed.