Amid the global economic crisis, the President's Emergency Plan for AIDS Relief (PEPFAR) and other organizations have been pressed to do more with constrained resources to meet unmet needs in the worldwide HIV/AIDS pandemic. PEPFAR has approached this challenge through the development of an Impact and Efficiency Acceleration Plan, which includes improving the collection and use of economic and financial data, increasing the efficiency of HIV/AIDS program implementation, and collaborating with governments and multilateral organizations to maximize the impact of the resources provided by the United States. For example, by linking financial data with program outputs, PEPFAR was able to help its implementing partners in Mozambique reduce mean unit expenditures for people receiving antiretroviral treatment by 45 percent, from $265 to $145 per person, between 2009 and 2011. This article describes the plan's elements, provides examples of progress and challenges to its implementation, and assesses the prospects for further improvements in efficiency and impact.