Type 2 diabetes is a heterogeneous disease characterized by multiple pathogenic defects. Impaired insulin secretion and insulin action (insulin resistance) are well-recognized major mechanisms contributing to the development of diabetes. In the past years, intensive research has much improved our understanding of the molecular mechanisms leading to defects of beta-cell function and impaired ability of insulin to promote glucose uptake in muscle and adipose tissue. More recently, other organs have been shown to play a role in the abnormalities of glucose homeostasis. The discovery that the gut, following the ingestion of nutrients, releases factors (incretins) that augment the response of the beta cell and suppress glucagon secretion has opened a whole new area of active investigation to understand its role in glucose homeostasis. The introduction of GLP-1 based therapies is the direct consequence of these discoveries. The role of inappropriate glucagon concentration has found renewed interest as a mechanism contributing uncontrolled hepatic glucose production. Moreover, new players have come onto the stage of the pathogenesis of type 2 diabetes. Maladaptive processes occur at the level of the kidney that may lead to inappropriate reabsorption of glucose in the presence of hyperglycaemia. Finally (for the moment!), more is being learned about the central control of metabolic and hormonal responses by the brain. Cristina Bianchi and Stefano Del Prato from Pisa, Italy, review the changing scene.