Antithrombin is the most important physiological inhibitor of the various activated serine protease clotting factors, particularly thrombin. In vitro, the inhibition of thrombin by antithrombin is very slow; but greatly enhanced by heparin and related glycosaminoglycans. When a serine protease interacts with antithrombin, the two proteins form a covalent stable stoichiometric 1:1 complex that is rapidly removed from the circulation. The formation of this stable covalent complex involves the cleavage of the reactive centre of the inhibitor at arginine 393-serine 394 by the active site serine residue of the protease. This is followed by the formation of an ester linkage between the active site serine residue of the protease and the arginine 393 residue of the cleaved antithrombin molecule. The existence of an antithrombin deficiency state was first recognized in 1965, in a family some of whose members suffered from recurrent episodes of venous thrombosis. Subsequently, many kindreds with antithrombin deficiency have been described from diverse geographic locations. Moreover, the prevalence of antithrombin deficiency in the general population has been reported to vary from 1:500 to 1:5000. With the advent of recombinant DNA techniques, the definition of the molecular pathology of antithrombin deficiency has allowed the characterization of the specific mutation in more than 150 kindreds. Approximately 60 different mutations, resulting in either an absent or a pathological antithrombin gene product, have been reported. Inherited antithrombin deficiency is a well-recognized cause of predisposition to venous thrombosis and in a large type 2 antithrombin-deficient kindred with an alanine 382 threonine mutation (antithrombin-Hamilton), less than 20% of affected individuals were found to have objective evidence for past thrombotic events. In most of these, the initial thrombotic episode occurred when a predisposing factor was present (pregnancy, surgery, oral contraception, trauma, etc.). The incidence of thrombotic events in subjects with inherited antithrombin deficiency thus appears to be significantly lower than heretofore estimated; moreover, such events appear to occur predominantly in association with predisposing factors. Insights from studies of patients with inherited antithrombin deficiency could provide useful information in the management of those with acquired antithrombin deficiency.