The central therapeutic problem in diabetes mellitus is prevention and treatment of the chronic vascular disease associated with this disorder. Prolonged exposure to hyperglycemia is the primary factor associated with the development of diabetes-specific microvascular disease, and the relationship between deranged glucose metabolism and arterial disease is complicated by many other factors that influence atherogenesis in nondiabetics. Until relatively recently, knowledge about diabetic vascular disease was limited mainly to clinical description. New information about abnormal vascular physiology, ultrastructure, biochemistry, cell biology, and molecular biology now makes it possible to understand in an integrated fashion the major specific mechanisms by which hyperglycemia damages diabetic vessels. Continued progress in this area will further optimize the development of safe and effective drugs for the treatment of diabetic vascular disease.