Under normal conditions the blood circulates freely within the confines of the vascular system, carrying oxygen, nutrients, and hormonal information around the body and removing metabolic waste. If blood gains access to extravascular sites, or the vasculature becomes pathologically challenged, hemostasis may be activated. This process is finely regulated by positive and negative feedback loops that modulate fibrin clot formation. Blood coagulation revolves around the activation and assembly of the components of the prothrombinase complex, which converts the inactive zymogen, prothrombin, into its active form, thrombin. This serine protease catalyzes the conversion of fibrinogen to fibrin, the structural scaffold that stabilizes platelet aggregates at sites of vascular injury. The extent of the hemostatic response is controlled by the action of inhibitory pathways, which ensure that thrombin activity and the spread of the hemostatic plug is limited to the site of vessel damage. This review article focuses on the major physiological regulator of tissue factor–induced coagulation, tissue factor pathway inhibitor, its expression, anticoagulant function, and its role in normal hemostasis.