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The report examines the steep and historic expansion of U.S. health engagement in Africa, principally through the President’s Emergency Plan for AIDS Relief (PEPFAR) and the President’s Malaria Initiative (PMI), in the past decade. This dramatic shift in U.S. foreign assistance—spurred by the “exceptionalism” of HIV/AIDS—has rested on a consensus that substantial U.S. investments in health in Africa do indeed advance U.S. interests. They fulfill American humanitarian values by saving and enhancing lives; they strengthen health security against common and emerging threats; and they promote the stability and long-term development of vulnerable communities in low-income countries. Despite the achievements of U.S. global health programs over the past decade, challenges remain.