The extent to which clinical and public health guidance developed by the National Institute for Health and Clinical Excellence (NICE) can effectively serve the public by improving quality and efficiency across the National Health Service (NHS) and the broader public sector depends largely on the quality and relevance of the available evidence which informs its decisions. There are well-established organizational and procedural links between NICE and academic and professional organizations that undertake evidence synthesis. However, there are fewer means for evidence gaps identified during the development of NICE guidance to lead to the commissioning of new prospective studies. In this paper, we discuss the importance of a publicly funded clinical and public health research agenda that includes new prospective studies aimed at addressing knowledge gaps identified by NICE. We describe the early experience of NICE and the National Institute for Health Research (NIHR) working together to articulate and commission research to inform best practice recommendations. We propose ways in which NICE can collaborate more effectively with research funders to improve the evidence base upon which it bases its recommendations.