President's Emergency Plan for AIDS Relief (PEPFAR's) response to the millions of children impacted by HIV/AIDS was to designate 10% of its budget to securing their futures, making it the leading supporter of programs reaching orphan and vulnerable children (OVC) programs globally. This article describes the evolution of PEPFAR's OVC response based on programmatic lessons learned and an evergrowing understanding of the impacts of HIV/AIDS. In launching this international emergency effort and transitioning it toward sustainable local systems, PEPFAR helped establish both the technical content and the central importance of care and support for OVC as a necessary complement to biomedical efforts to end the HIV/AIDS epidemic. Critical services are reaching millions of HIV-affected children and families through vast networks of community-based responders and strengthened national systems of care. But rapid program scale-up has at times resulted in inconsistent responses, failure to match resources to properly assessed needs, and a dearth of rigorous program evaluations. Key investments should continue to be directed toward more sustainable and effective responses. These include greater attention to children's most significant developmental stages, a focus on building the resilience of families and communities, a proper balance of government and civil society investments, and more rigorous evaluation and research to ensure evidence-based programming. Even as HIV prevalence declines and medical treatment improves and expands, the impacts of HIV/AIDS on children, families, communities, economies, and societies will continue to accumulate for generations. Protecting the full potential of children-and thus of societies-requires sustained and strategic global investments aligned with experience and science.