Vascular Calcification (VC) is the major contributors of Cardiovascular (CV) morbidity and mortality in patients with established Coronary Artery Disease (CAD), diabetes mellitus and Chronic Kidney Disease (CKD). Amongst several factors in abundant involved in the molecular mechanisms of regulation of ectopic calcification, Osteopontin (OPN) appears to be promised, while its role in the VC is controversial. OPN is chemokine-like matricellular phosphor glycol proteins with abilities to regulate inflammation, bone formation, hematopoiesis, and angiogenesis. It is known that the elevated circulating level of OPN may independently predict VC in subjects with established CAD, diabetes mellitus and CKD. The peak concentration of OPN in peripheral blood used to assay aimed to assume the risk of the CV-related clinical outcomes. The editorial recaps our knowledge regarding OPN as a biological marker of VC with possible predictive value.