Clot formation is the final result of interaction among multiple plasma proteins; after activation, it results in the conversion of fibrinogen to fibrin and cross-linking of fibrin by activated factor XIII, which stabilizes the formed clot. Deficiency or functional abnormality of the factors involved in these reactions causes bleeding disorders. Natural inhibitors of clotting factors include antithrombin III, protein S, and protein C. When activated, these proteins inactivate specific clotting factors, providing a regulatory mechanism that serves to control the coagulation response and limit the extension of the clot. Physiologic or natural inhibitors should not be confused with acquired inhibitors of coagulation factors, which are discussed in this review. Inhibitors to coagulation factors, also known as circulating anticoagulants, are antibodies that neutralize specific clotting proteins, thereby interfering with their normal function. Antibodies may be directed against isolated clotting factors, as is the case with factor VIII or IX inhibitors. On the other hand, the antiphospholipid antibodies are known to develop against multiple coagulation proteins. In contrast to patients with antibodies against isolated clotting factors, who commonly present with spontaneous bleeding, individuals with antiphospholipid antibodies may be asymptomatic or present with venous or arterial thrombosis. In this article I refer to inhibitors developing in patients with hemophilia A or other congenital factor deficiency as alloantibodies, and to spontaneous formation of antibodies in patients without prior history of hemorrhagic diathesis as autoantibodies. The antiphospholipid antibodies are discussed separately.