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The goal of this review is to present an update on basic and epidemiological findings associating variants in prothrombotic genes with atherogenesis and atherothrombotic disease.The relation between atherosclerosis and thrombosis has long been recognized but only recently has it been understood that certain hemostatic factors affect not only thrombus formation, but also have a direct atherogenic role. Atherosclerosis is a complex disorder that results from the interaction of multiple genetic and environmental factors. Numerous polymorphisms and mutations in genes related to the hemostatic system and to vascular redox determinants that modulate nitric oxide bioavailability have been identified in the past decade; their role in atherogenesis and the risk of cardiovascular disease, however, remain uncertain. We will discuss the functional implications and association with disease risk of polymorphisms in coagulation factors (fibrinogen, prothrombin, and factor V); fibrinolytic factors (plasminogen activator inhibitor 1 and lipoprotein(a)); platelet surface receptors; and vascular redox determinants (methylenetetrahydrofolate reductase, endothelial nitric oxide synthase, and the antioxidant enzymes cellular glutathione peroxidase and paraoxonase).Overall, these genetic variants have a modest effect on risk when considered individually but gain potency when acting synergistically with other genetic or environmental risk factors. We conclude that a better characterization of these interactions, in addition to the identification of potential novel genetic determinants, constitute key issues in the future understanding of the pathogenesis of atherothrombosis.