The patients with metabolic syndrome or type 2 diabetes mellitus are characterized by insulin resistance and have more risks to develop extensive atherosclerosis, even it occurs before hyperglycemia. Atherosclerosis is the leading cause of death in diabetic population. Thus it is important to explore the mechanisms of atherosclerosis. Besides the traditional risk factors, C-peptide which is considered no biological activity may play role in atherogenesis. It involves inflammation of artery and results in monocyte/macrophage accumulation as well as smooth muscle cell proliferation. Several cohort studies suggest that increased C-peptide levels relate to all-cause death, cardiovascular disease and cancer mortality.This review focuses on the new biological functions of C-peptide based on in vitro, vivo research and clinical studies.