Worldwide, >1000 children are newly infected with human immunodeficiency virus (HIV) each day; the majority of these children are in sub-Saharan Africa. The primary mode of HIV acquisition is through mother-to-child transmission (MTCT) during pregnancy, childbirth, or breastfeeding. In well-resourced health care systems, like those in the United States, universal HIV testing for pregnant women, provision of antiretroviral therapy (when needed for maternal health) or prophylaxis, elective cesarean delivery, and avoidance of breastfeeding has reduced MTCT of HIV infection to 1%-2%. However, in resource-limited countries, the perinatal epidemic continues generally unabated. Clinical trials have identified simple, less expensive, effective antiretroviral prophylaxis regimens that can be implemented in resource-limited settings. However, implementation has been slow, and postnatal transmission of HIV through breastfeeding remains a significant challenge. This article will review the research on prevention of MTCT of HIV infection in resource-limited countries and the challenges to expansion of the benefits of preventive interventions for MTCT throughout the world.