Hyperglycemia is considered a key causal factor in the development of diabetic vascular complications and can mediate its adverse effects through multiple pathways. This was confirmed for microangiopathy in the Diabetes Control and Complications Trial study for type 1 diabetes and corroborated for type 2 diabetes by the United Kingdom Prospective Diabetes Study published in 1998. Prevention of diabetic complications requires at least control of glycemia. This article briefly summarizes the evidence that strongly supports the role of hyperglycemia in vascular complications. After outlining the role of the polyol pathway, protein kinase C, and oxidative stress, the author focuses on one of the key biochemical mechanisms for this pathologic process: the direct deleterious action of glucose and other sugars on proteins, known as glycation or nonenzymatic glycosylation. Results of animal studies and phase III clinical trials reveal that the inhibition of this process attenuates the development of a range of these complications.