The OPG/RANK/RANKL axis is now recognized as a master regulator of bone remodeling, controlling osteoclast's maturation and extracellular matrix calcification. Nevertheless, a number of clinical and basic science studies conducted in the last few years demonstrated that the triad could be also involved in several physiological and pathological processes outside the bone tissue. In particular, evidences have been collected showing an active participation of OPG and RANKL in vascular pathology, including atherogenesis and arterial calcification. A series of epidemiological studies also showed that increased circulating levels of OPG are associated with significant, independent predictive value for future cardiovascular mortality/morbidity. However, the human studies did not unravel whether OPG should be considered as a promoter, a protective mechanism or is instead neutral with regard of vascular disease progression. Main objective of the present review is to summarize findings from both in vivo and in vitro investigations on the role played by OPG in vascular disease progression and to delineate a plausible scenario on the actual involvement of the OPG/RANK/RANKL triad and TRAIL in cardiovascular pathology.