Osteoprotegerin (OPG) is a 401 amino acid N-glycosylated protein, which is highly expressed in a large number of tissues. OPG mainly binds to two ligands, i.e. RANKL (receptor activator of nuclear factor κB ligand) and TRAIL (tumor necrosis factor- related apoptosis-inducing ligand). Upon binding to the former ligand, OPG inhibits the activation of osteoclasts and promotes apoptosis of osteoclasts, whereas the binding of OPG with TRAIL prevents apoptosis of tumor cells. There is now emerging evidence that OPG participates in the pathogenesis of atherosclerosis and cardiovascular diseases by amplifying the adverse effects of inflammation and several traditional risk factors such as hyperlipidemia, endothelial dysfunction, diabetes mellitus, and hypertension. Some epidemiological studies also showed a positive association between OPG levels and cardiovascular morbidity and mortality. The aim of this article is to provide an overview of the main biochemical, physiological, and pathological aspects of OPG biology in cardiovascular disease.