In South Africa according to the 2013 mid-year population estimates the overall HIV prevalence is 10% with the total number of people living with HIV-infection estimated at approximately 5.26 million. Thus Southern Africa has been declaring a long war against the HIV epidemic and South Africa is still bearing the brunt of this epidemic. In sub-Sharan Africa, where there is ongoing prevention-of-mother-to- child transmission (PMTCT) of HIV infection and disease, there remains an expanding number of young individuals who will spend the rest of their lifetime coping with the reality of HIV infection, being managed with a chronic disease and expected to remain on lifetime chronic antiretroviral medication. The effects on HIV infected children and adolescents are multi-faceted and complex, but emerging problems such as HIV drug resistance and transition programme difficulties with distant and perhaps unknown goals need to be tackled. In addition, as children are growing and maturing with HIV- infection and being treated with long-term antiretroviral medication and regimens, more clinical complications, other than death, and complications of their medications are observed, including cardiac diseases, malignancies, growth failure, a wide range of skin diseases, renal and bone complications, neurocognitive problems, co-infections, neuropsychiatric co-morbidities, dyslipidaemias and earlier lung conditions. Practical issues regarding disclosure to young HIV-infected individuals, transitioning care and HIV-infection in the adolescent years will be addressed and this article will highlight certain considerations, including caring and monitoring of children and adolescents living with HIV, exposing vulnerable populations, establishing research interests and identifying some challenges between resource-rich and resource-poor settings.