T2DM (Type 2 diabetes mellitus) has reached epidemic proportions worldwide, exerting major health consequences at an individual and public health level alike. Unfortunately, the molecular pathophysiology of diabetes remains incompletely understood, impairing progress towards more effective prevention and treatment strategies. Although the rapid increase in the prevalence of insulin resistance and T2DM over the past several decades highlights a major environmental contribution related to overnutrition, obesity and inactivity, susceptibility is likely to reflect individual differences in complex gene–environment interactions. In the present review, we focus on mediators of genetic and environmental risk for T2DM at a molecular level.