Prevention of long-term complications remains the main challenge in the treatment of diabetes. A strong relationship between glucose control and development of complications is apparent in all epidemiologic studies. Yet, intervention trials have yielded questionable results, particularly when intensive treatment was introduced in patients with long-standing diabetes. It has been postulated that in these subjects, prior exposure to chronic hyperglycemia may have generated a negative "metabolic memory," preventing full exertion of the beneficial effects of any subsequent improvement of glucose control. This phenomenon has been replicated in animal models and it recognizes a molecular basis in the role of oxidative stress, advanced glycation processes, and epigenetic mechanisms accounting for self-perpetuating modifications of gene expression. Conversely, early intervention in both type 1 and type 2 diabetes has proven that good glycemic control reduces the risk of development and progression of complications with a beneficial effect that extends well beyond the duration of near-normoglycemia. This has brought up the concept of "metabolic legacy," an advantage handed down by early and effective implementation of treatments designed to reduce blood glucose levels as safely as possible along with multifactorial intervention of all cardiovascular risk factors. The evidence, nature, and clinical implication of these concepts are reviewed.