An estimated 430,00 new human immunodeficiency virus (HIV) infections occurred among children younger than 15 years of age in 2008, most in sub-Saharan Africa and most due to mother-to-child transmission (MTCT). In marked contrast, MTCT of HIV has been virtually eliminated in well-resourced settings through the use of combinations of antiretroviral (ARV) drugs for the mother during pregnancy and labor and for the infant postpartum; cesarean delivery to reduce the infant’s exposure to trauma and infection in the birth canal; and formula feeding to protect the infant from transmission from breastfeeding. While effective, these interventions are costly and require strong health-care systems. From 1999 to 2003, Horizons conducted operations research to determine how interventions successful in the clinical trial setting would translate to the real-world environments of maternal and child healthcare delivery in low-resource settings. A second set of Horizons studies (2004–2007) sought to address gaps in adherence to ARV prophylaxis; examine roles of family planning in prevention of MTCT (PMTCT) programs; show the value of psychosocial support for HIV-positive mothers; and identify ways to improve the quality of care and follow-up for women in the postpartum period. This article provides an assessment of the findings of Horizons studies on PMTCT interventions from 1999 to 2007 and identifies needs for follow-on efforts.