The President's Emergency Plan for AIDS Relief (PEPFAR) has made a major contribution to the reduction of the global HIV/AIDS burden. The program initially focused on rapidly scaling up treatment and prevention services in fifteen low-income countries, then transitioned to an approach that emphasizes sustainability, defined as the capacity to maintain program services after financial, managerial, and technical assistance from the United States and other external donors essentially ceases. Today, PEPFAR continues to expand its HIV prevention, treatment, and care activities while also supporting capacity-building initiatives, coordination efforts, and implementation science. The latter is research focused on improving service delivery, maximizing cost-effectiveness, and achieving public health impact. Recent advances in both scientific knowledge and the provision of prevention, treatment, and care services have bred cautious optimism about greatly reducing the spread of HIV. However, success will require a substantial increase in resources, strengthened health systems, renewed commitment to HIV prevention, and well-financed efforts to develop an effective HIV vaccine.