During the past decade, improved understanding of the pathophysiological mechanisms of diabetes development has resulted in advances in therapeutic concepts, but has also supported the potential for diabetes prevention through nonpharmacological means. At the beginning of the century, we experienced a shift in paradigm, as landmark studies have shown that diabetes mellitus is preventable with lifestyle intervention; moderate changes in diet and physical activity produce a substantial and sustained reduction in the incidence of type 2 diabetes mellitus (T2DM) for individuals with impaired glucose tolerance. This evidence must now be translated into clinical and public-health practice, but translational studies have varied in their ability to replicate the results of clinical trials. This variation reflects a number of challenging barriers for diabetes prevention in real-world clinical practice, which makes it necessary to focus on identifying efficient intervention methods and delivery mechanisms. Research is now focusing on these mechanisms, as well as on developing efficient screening and risk-identification strategies and realistic scenarios for public-health policy to implement diabetes prevention programs. In this Review, we will discuss these mechanisms and will consider the implications of diabetes prevention for public-health strategy and policy.