Abstract Atherosclerosis is a chronic inflammatory process of the vessel wall with systemic correlates. It is now well established that patients' outcome is tightly linked to atherosclerotic plaque stability, potentially more so than to the mere plaque size. Osteopontin (OPN) is an integrin-binding ligand, N-linked glycoprotein, which was recognized as a significant participant in the atherosclerotic inflammatory milieu. Evidence from several genetic mouse models suggests that OPN is an enhancer of atherosclerosis. This may be mediated by its capacity to enhance inflammation in the atherosclerotic plaque. Interestingly, OPN may also possess potentially protective vascular effects, such as attenuation of vascular calcification. In humans circulating levels of OPN were found to be independently associated with the severity of coronary atherosclerosis. Moreover, several studies report that high plasma OPN levels were associated with increased risk for major adverse cardiac events. This review aims to critically assess current understanding of the role of OPN in the atherosclerotic process, from animal models to clinical practice. Specific focus is given to evaluating whether OPN could serve as a marker for monitoring coronary atherosclerosis severity, and in parallel, assess the evidence for its role as a mediator in the pathogenic pathways leading to atherosclerotic vascular disease.