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In most countries, the burden of HIV among people who inject drugs, men who have sex with men, and sex workers is disproportionately high compared with that in the general population. Meanwhile, coverage rates of effective interventions among those key populations (KPs) are extremely low, despite a strong evidence base about the effectiveness of currently available interventions. In its first decade, President's Emergency Plan for AIDS Relief (PEPFAR) is making progress in responding to HIV/AIDS, its risk factors, and the needs of KPs. Recent surveillance, surveys, and size estimation activities are helping PEPFAR country programs better estimate the HIV disease burden, understand risk behavior trends, and determine coverage and resources required for appropriate scale-up of services for KPs. To expand country planning of programs to further reduce HIV burden and increase coverage among KPs, PEPFAR has developed a strategy consisting of technical documents on the prevention of HIV among people who inject drugs (July 2010) and prevention of HIV among men who have sex with men (May 2011), linked with regional meetings and assistance visits to guide the adoption and scale-up of comprehensive packages of evidence-based prevention services for KPs. The implementation and scaling up of available and targeted interventions adapted for KPs are important steps in gaining better control over the spread and impact of HIV/AIDS among these populations.