: The scale-up of antiretroviral prophylaxis to prevent mother-to-child transmission of HIV has significantly reduced new pediatric infections in sub-Saharan Africa. However, among infants who become HIV-infected despite prevent mother-to-child transmission, more than 50% have drug-resistant HIV. Given high levels of resistance, WHO recommends the use of protease inhibitors as part of first-line pediatric antiretroviral therapy (ART) to optimize treatment response, but costs and logistic challenges restrict access. A great concern is the current lack of ART options for children who experience virological failure. In this opinion article, we argue that enhanced efforts are needed to help contain the emergence of pretreatment resistance in children and hence improve ART outcomes. The vertical transmission of (drug-resistant) HIV can be prevented through enhancing ART adherence and frequent viral-load testing during pregnancy and throughout breast-feeding. Pretreatment resistance, due to the use of subtherapeutic infant prophylaxis or exposure to suboptimal maternal ART through breast-feeding, can be prevented by the use of effective antiretroviral prophylaxis, based on either triple-drug combination or high genetic-barrier drugs, coupled with early infant diagnosis and prompt ART initiation. Further research is needed to assess programmatic barriers and cost-effectiveness of such strategies.