When normal endothelial function is shifted to a pathological degree, the foundation is laid for possibly following diseases. This endothelial dysfunction is characterized by a proinflammatory state, reduced vasodilation, and a prothrombotic state. In the continuation this dysfunction is strongly associated cardiovascular morbidity and mortality. Endothelial dysfunction is markedly enhanced in type 2 diabetes providing a major pathophysiological cause for the massively increased cardiovascular risk of diabetic patients. Subsequently future therapeutic approaches for the treatment of diabetic cardiovascular disease should target the dysfunctional endothelium first.