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Since its inception in 2003, the US President's Emergency Plan for AIDS Relief (PEPFAR) has been an important driving force behind the global scale-up of HIV care and treatment services, particularly in expansion of access to antiretroviral therapy. Despite initial concerns about cost and feasibility, PEPFAR overcame challenges by leveraging and coordinating with other funders, by working in partnership with the most affected countries, by supporting local ownership, by using a public health approach, by supporting task-shifting strategies, and by paying attention to health systems strengthening. As of September 2011, PEPFAR directly supported initiation of antiretroviral therapy for 3.9 million people and provided care and support for nearly 13 million people. Benefits in terms of prevention of morbidity and mortality have been reaped by those receiving the services, with evidence of societal benefits beyond the anticipated clinical benefits. However, much remains to be accomplished to achieve universal access, to enhance the quality of programs, to ensure retention of patients in care, and to continue to strengthen health systems.