In the last 50 years health care systems throughout the world have faced a new epidemic dual disease: cardiovascular disease (CVD)-diabetes mellitus. Nowadays, CVD is the leading cause of death in all western countries, and 60% of deaths for ischemic heart disease and stroke occur in developing countries with fixing resources. The striking association between CAD, stroke, peripheral artery disease and diabetes, since the publication of the first large-scale epidemiologic investigation in the 1970s, has forced physicians to investigate the possible pathophysiological connection among these diverse clinical conditions. Recent and compelling evidence has shown the significant and independent role of inflammation, insulin resistance and subsequent endothelial dysfunction in the initiation and progression of atherothrombosis, superimposed on traditional risk factors. Given the up-to-date molecular data linking diabetes, endothelial dysfunction, inflammation, and atherosclerosis, this review will focus on the common mechanisms underlying these conditions and on new promising therapeutic strategies.