Diabetic macroangiopathy, atherosclerosis secondary to diabetes mellitus (DM), causes cerebro-cardiovascular diseases, which are major causes of death in patients with DM and significantly reduce their quality of life. The alterations in vascular homeostasis due to endothelial and vascular smooth muscle cell dysfunction are the main features of diabetic macroangiopathy. Although multiple metabolic abnormalities that characterize diabetes are involved in the progression of atherosclerosis in patients with DM, it may be said that prolonged exposure to hyperglycemia and insulin resistance clustering with other risk factors such as obesity, arterial hypertension, and dyslipidemia play crucial roles. Laboratory and clinical researches in the past decades have revealed that major biochemical pathways involved in the development of diabetic macroangiopathy are as follows: overproduction of reactive oxygen species, increased formation of advanced glycation end-products (AGEs) and activation of the AGEs-receptor for AGE axis, polyol and hexosamine flux, protein kinase C activation, and chronic vascular inflammation. Among them, oxidative stress is considered to be a key factor.