Efforts to prevent the mother-to-child transmission (PMTCT) of HIV infection have encountered remarkable successes and considerable challenges around the globe. The reductions in vertical HIV transmission observed in Europe and North America have helped raise the possibility of the virtual elimination of new pediatric HIV infections and in turn an “AIDS-free generation”. Yet in many resource-limited settings, preventable new pediatric infections continue to occur daily. Here, we consider what will be required to reach an end to the global pediatric HIV epidemic, and what we can hope for in the context of resurgent international interest. The science of PMTCT has advanced dramatically since the first evidence for the use of antiretroviral (ARV) drugs for PMTCT in 1994. The timing and causes of vertical transmission are now well understood, and this knowledge has led directly to highly efficacious PMTCT interventions based on the use of combination ARV regimens. The application of these interventions around the world has been uneven, however. Several African countries report good access to and uptake of PMTCT services and corresponding low rates of early mother-to-child transmission. However, limited population coverage of PMTCT programs with continued use of suboptimal ARV regimens still hamper prevention efforts in many other countries. Looking forward, reaching ambitious international targets to reduce pediatric HIV infections will require a combination of increased access to efficacious ARV regimens and strengthened health systems for maternal and child health, supported by continued strong political will and international attention.