The purpose of this article is to review prominent studies on HIV drug-resistance in mothers and their infants after the use of antiretroviral drugs to prevent mother-to-child-transmission in resource-limited communities. The effects of drug-resistance on subsequent combination antiretroviral therapy are discussed, as are the probable mechanisms of acquisition and decay or persistence of drug-resistant mutants. Differences in the rates of HIV drug-resistance from interventions used to prevent mother-to-child-transmission in North America and Europe are contrasted to the simplified regimens used in resource-limited settings. Unresolved issues related to HIV drug-resistance are reviewed, including: whether maternal zidovudine monotherapy selects significant resistance; the clinical relevance of HIV drug-resistant variants selected by single-dose nevirapine that persist as minority viral variants and can affect the outcome of nonnucleoside reverse transcriptase inhibitor-based therapy; and the use of maternal combination antiretroviral therapy during breastfeeding. Finally, the current and upcoming strategies to reduce HIV drug-resistance related to use of antiretrovirals to prevent mother-to-child-transmission are discussed and contrasted with the challenges of financing and administering antiretrovirals to prevent mother-to-child-transmission in resource-limited communities.