In the last years type 2 diabetes has reached almost epidemic proportions. More than 170 million individuals are affected worldwide, about 6 million in Germany. In the pathogenesis of type 2 diabetes, insulin resistance in liver, fat and muscle as well as the inability of the pancreatic beta-cell to fully compensate for this insulin resistance are the central pathophysiological events. Both genetic and environmental factors, such as lack of physical exercise and hypercaloric nutrition play a major role in this process, although the precise mechanisms for type 2 diabetes development remain largely unknown. In the characterization of the role of liver, adipose tissue and skeletal muscle in the pathogenesis of type 2 diabetes, tissue specific knockout mouse models have challenged our concepts of glucose homeostasis.