With antiretroviral therapy (ART) recommended by the World Health Organization (WHO) for children aged <2 years with human immunodeficiency virus (HIV) and continuing global ART roll-out, ART coverage in children is rising. However ART coverage in children lags considerably behind that in adults (28% vs 58%). Long duration of therapy needed for HIV-infected children requires maximal efficacy, minimal toxicity, and prevention of development of drug resistance. This requires consideration of ways to improve sequencing of regimens during childhood to minimize development of resistance and treatment failure. We consider aspects of virological failure and development of resistance in vertically HIV-infected children in resource-limited settings. We review evidence guiding choices of first- and second-line ART, the impact of drugs given to prevent mother-to-child transmission, adherence issues and, availability of appropriate drug formulations. Recommendations made during the Collaborative HIV and Anti-HIV Drug Resistance Network (CHAIN)/WHO meeting (October 2012) are summarized.