To meet the ambitious targets set by the Global Plan Towards the Elimination of New HIV Infections Among Children by 2015 and Keeping Their Mothers Alive (Global Plan), the initial 22 priority countries quickly developed innovative approaches for overcoming long-standing health systems challenges and providing HIV testing and treatment to pregnant and breastfeeding women and their infants. The Global Plan spurred programs for prevention of mother-to-child HIV transmission to integrate HIV-related care and treatment into broader maternal, newborn, and child health services; expand the effectiveness of the health workforce through task sharing; extend health services into communities; strengthen supply chain and commodity management systems; reduce diagnostic and laboratory hurdles; and strengthen strategic supervision and mentorship. The article reviews the ongoing challenges for prevention of mother-to-child HIV transmission programs as they continue to strive for elimination of vertical transmission of HIV infection in the post-Global Plan era. Although progress has been rapid, health systems still face important challenges, particularly follow-up and diagnosis of HIV-exposed infants, continuity of care, and the promotion of services that are respectful and client centered.