HIV-1 infection is one of the leading causes of childhood morbidity and mortality globally and mother-to-child transmission (MTCT) is the major mode of infection. Over the past decade, natural history and interventional studies have improved our understanding of the pathogenesis of MTCT and pediatric HIV-1 infection. This has resulted in the development of effective preventive strategies to reduce new infections and therapeutic strategies to improve outcome following infection. However, successful implementation of these preventive and therapeutic strategies has been limited in resource-poor settings, where the majority of new pediatric infections occur. In addition, toxicities and antiretroviral resistance may limit the long-term utility of currently available strategies. Continued efforts to understand MTCT and pediatric HIV-1 pathogenesis and to refine preventive and therapeutic strategies are of high priority.