Cardiovascular diseases are the major causes of morbidity and mortality in people with diabetes. Macroangiopathy in diabetes is manifested by more accelerated and progressive atherosclerosis, which is more widely distributed. The pathogenesis of this accelerated atherosclerosis is multifactorial and includes very complex interactions. Several abnormalities - such as hyperglycemia, dyslipidemia, hypertension, endothelial dysfunction, renin-angiotensin system activation and chronic subclinical inflammation - all appear to play important roles in the development of diabetes-induced atherosclerosis. Treatment of the residual risk, other than glycemia, blood pressure and low-density lipoprotein cholesterol, remains important as the rate of diabetes increases worldwide. A synergistic multifactorial approach against both conventional cardiovascular risk factors and emerging risk factors, such as vasoactive systems, the AGE-RAGE axis, novel proteins, such as TRAIL, and the complement system, as well as oxidative stress and inflammation, may be a promising way to prevent macrovascular disease in diabetes. In this review we focus on the major causes and mechanisms of atherosclerotic disease in patients with diabetes and highlight emerging targets for therapeutic intervention.