Despite the availability of multiple therapeutic approaches, diabetes mellitus with chronic hyperglycemia remains as the main cause of new cases of blindness and chronic renal failure in the western hemisphere. We herein review the molecular mechanisms by which chronic hyperglycemia causes retinopathy and nephropathy in type I and type 2 diabetic patients. Diabetic retinopathy develops silently along years or decades, producing symptoms only in its very late stages. Its slow development starts with the activation of aldose reductase, shortly followed by the destruction of the retinal pericyte cells, and ends in sudden blindness when vitreous hemorrhage ensues. Nephropathy, on the other hand, centers its pathophysiology in the mesangial cell, that starts as a modified smooth-muscle cell, and turns itself into a myo-fibroblast, produces such amounts of cytoplasm and extracellular protein that strangulates the glomerular capillaries and causes renal failure. After a detailed review of the molecular mechanisms of the aforementioned complications, we conclude that, apart from directing our attention to the emerging medications that are being developed to block these molecular pathways, we should never abandon the struggle for improving the glycemic control of our diabetic patients.