In patients with diabetes, atherosclerosis is the main reason for impaired life expectancy, and diabetic nephropathy and retinopathy are the largest contributors to end-stage renal disease and blindness, respectively. An improved therapeutic approach to combat diabetic vascular complications might include blocking mechanisms of injury as well as promoting protective or regenerating factors, for example by enhancing the action of insulin-regulated genes in endothelial cells, promoting gene programs leading to induction of antioxidant or anti-inflammatory factors, or improving the sensitivity to vascular cell survival factors. Such strategies could help prevent complications despite suboptimal metabolic control.