Diabetes mellitus is a multifactorial disease, classically influenced by genetic determinants of individual susceptibility, and by environmental accelerating factors, such as lifestyle. It is considered a major health concern as its incidence is increasing at an alarming rate, and the high invalidating effects of its long-term complications affecting macro- and micro-vasculature, heart, kidney, eye, and nerves. Increasing evidences indicate that hyperglycemia is the initiating cause of tissue damage occurring in diabetes, either through repeated acute changes in cellular glucose metabolism, or through the long-term accumulation of glycated biomolecules and advanced glycation end products (AGE). AGE represent a heterogenous group of chemical products resulting from a nonenzymatic reaction between reducing sugars and proteins, lipids and/or nucleic acids. The glycation process (glucose fixation) affects circulating proteins (serum albumin, lipoprotein, insulin, haemoglobin), while the formation of AGE implicates reactive intermediates such as methylglyoxal. AGE form cross-links on long-lived extracellular matrix proteins, or react with specific receptors RAGE, resulting in oxidative stress and proinflammatory signaling implicated in endothelium dysfunction, arterial stiffening, and microvascular complications. This review summarizes the mechanism of glycation and of AGE formation, and the role of hyperglycemia, AGE and oxidative stress in the pathophysiology of diabetic complications.