The Institute of Medicine has recommended that policy decisions about improvement of national public health systems be guided by sound scientific evidence. However, to date there is no national research agenda to help guide public health systems. The Centers for Disease Control and Prevention was called upon to lead a collaborative consensus-based process to define key research questions and establish a framework to create opportunities to better coordinate, leverage, and identify public health resources, which are increasingly scarce. The public health systems research agenda that emerged from this process has 14 over-arching priority research themes. This national agenda should stimulate and guide research to meet the urgent need to improve the nation's public health systems.