In 2010 the US federal government will have spent more than $150 billion on research and development. What gets done with that enormous sum has important implications for the wide variety of problems facing our society today and in the years to come. Important decisions on challenges like national defense, environmental change, rapid urbanization, and public health rely on scientific knowledge to inform them. Given the complexity and the significance of such challenges, how can science funders effectively orient a vast research enterprise to make real progress toward desired social goals?