The United States President's Emergency Plan for AIDS Relief (PEPFAR) has played a key leadership role in the global response to the HIV/AIDS pandemic. PEPFAR was inspired by the principles of the historic Monterrey Consensus (United Nations. Monterrey Consensus on Financing for Development, Monterrey, Mexico, March 18-22, 2002. New York: United Nations; 2002. Available at: http://www.un.org/esa/ffd/monterrey/MonterreyConsensus.pdf. Accessed April 21, 2012), which changed the underlying conceptual framework for international development, and therefore global health--a shift from paternalism to partnership that begins with country ownership and requires good governance, a results-based approach, and engagement of all sectors of society. PEPFAR began with a focus on the growing emergency of the HIV/AIDS pandemic by rapidly expanding HIV services, building clinical capacity, implementing strategic information systems, and building a coalition of partners to lead the response. Within the first years of implementation, there was a shift to sustainability, including the advent of Partnership Frameworks. The PEPFAR reauthorization in 2008 codified into law, the evolution in policies and programs for the next phase of implementation. In 2011 alone, PEPFAR supported nearly 4 million people on treatment, supported programs that provided more than 1.5 million HIV-positive pregnant women with antiretroviral drugs to prevent HIV transmission to their children, and supported HIV testing for more than 40 million people. This article provides an overview of how smart investments and partnerships across sectors and US agencies have helped achieve unprecedented results in increasing HIV/AIDS services and engaging partner countries and organizations in sharing the responsibility for an AIDS-free generation.