The Affordable Care Act of 2010 established the first-ever National Prevention, Health Promotion, and Public Health Council out of recognition of the need for a major new national focus on disease prevention. Composed of cabinet-level officials from a range of federal agencies, the council has a clear policy mandate: to coordinate and lead prevention, wellness, and health promotion efforts across the entire federal government and the nation. In its first year, the council developed a comprehensive prevention strategy; but its full implementation is threatened by economic, political, bureaucratic, and institutional challenges. This article examines these challenges and makes recommendations for how to maximize the positive impact of the council through effective cross-agency collaboration aimed at improving Americans' health, including framing prevention as a bipartisan cost containment strategy; distancing the work of the council from the implementation of other aspects of the Affordable Care Act; using dollars from the Prevention and Public Health Fund to incentivize ongoing participation by nonhealth agencies; and providing technical assistance and analytic support to nonhealth agencies willing to broaden attention to the health impacts of their nonhealth policies.