The National Diabetes Prevention and Control Program has a dynamic and evolving scientific foundation. This article describes this program and how seminal research studies provide an impetus for its public health policy and programs. The charge and challenges of integrating science into past, current, and future program designs are detailed, as are the program's accomplishments. Areas requiring new science are explored, including better research to translate new findings into clinical and public health practice and models to evaluate the effect of public health on improved outcomes. The epidemic of diabetes and its increasing burden on public health demands a better understanding of existing science and its limitations and informed public dialogue and policy responses.