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Atherosclerosis within 2 or more arterial beds has been termed polyvascular disease. Although polyvascular disease has long been associated with heightened cardiovascular risk, much is still unknown regarding its pathophysiology and management. In this past decade, the field of cardiovascular disease has experienced exponential growth in terms of antithrombotic and lipid-lowering therapies aimed at mitigating ischemic events. This review describes the inherent risk associated with polyvascular disease in contemporary observational and clinical trial populations and summarizes novel therapies in this high-risk population.