HIV prevention in the President's Emergency Plan for AIDS Relief (PEPFAR) began when both data on HIV prevalence and the toolbox of interventions for prevention of sexual transmission were relatively limited. PEPFAR's early focus was on scaling-up information, education, and communication programs that included messaging on abstinence for youth and faithfulness primarily through nongovernmental organizations, including faith-based organizations. Additional activities included condom promotion, distribution, and social marketing. In epidemics concentrated within key populations, PEPFAR's prevention efforts focused on a minimum package of services including outreach, information, education, and communication programs, STI treatment (where appropriate), and condom promotion and distribution. As more epidemiological data became available and with experience gleaned in these early efforts, the need for tailored and flexible approaches became evident. The next iteration of prevention efforts still emphasized behavioral interventions, but incorporated a sharper focus on key epidemic drivers, especially multiple partners; a data-driven emphasis on high transmission areas and populations, including prevention with people living with HIV; and a more strategic and coordinated approach at the national level. Recently, the paradigm for prevention efforts has shifted yet again. Evidence that biomedical interventions such as male circumcision, treatment for prevention of vertical and horizontal transmission, and treatment itself could lead to declines in incidence has refocused PEPFAR's prevention portfolio. New guidance on sexually transmitted HIV focuses on combination prevention, emphasizing biomedical, behavioral and structural approaches. Landmark speeches by the President and the Secretary of State and new ambitious targets for PEPFAR point toward a new goal: an AIDS-free generation.