During the past quarter century perhaps no single phenomenon has attracted so much attention in biology and medicine as blood clotting. It plays a role in numerous clinical conditions where it was not taken into account previously. Knowledge of the basic mechanisms recently passed through a tumulous stage of growth, but is now delineated in terms of simple enzymology. Most of the components have been obtained in purified form. There are three main events: the formation of autoprothrombin C (F-Xa, thrombokinase), the formation of thrombin, and the formation of fibrin. Prothrombin itself is a more marvelous protein than was predicted. It is a protein aggregate that contains the precursor of thrombin, the precursor of autoprothrombin C, as well as accessory protein. When blood coagulation is initiated by tissue injury, large amounts of autoprothrombin C activity arise in the presence of calcium ions and tissue thromboplastin. When there is no tissue injury, small amounts of autoprothrombin C are produced by platelet cofactor I (F-VIII, AHF) which functions with the lipids of platelets. Autoprothrombin C is the enzyme which produces thrombin activity, and being a part of the prothrombin aggregate it is in close proximity to the specific bond(s) that must be split to get thrombin activity. Although autoprothrombin C alone is sufficient to produce thrombin, the reaction is greatly accelerated by plasma Ac-globulin (F-V), lipids from platelets, and calcium ions. The acceleration produced by components functioning in pairs and relays makes possible the essential integration with the anatomic location of resources. Tissue materials pair with plasma resources to produce autoprothrombin C, and then they pair with another plasma component (Ac-globulin) to make autoprothrombin C function. In the absence of tissue injury, platelet materials pair with plasma resources to produce autoprothrombin C, and then platelets again work with another plasma component (Ac-globulin) to support the function of autoprothrombin C. Platelets are essential because their lipids are needed for the formation of autoprothrombin C, as well as for accelerating its function. Whatever involves platelets can be the stimulus to accelerate blood clotting; this includes Hageman factor. Platelets are the true point of beginning for the first step in blood clotting and are involved in the second and third. Vitamin K deficiency, or counteraction of Vitamin K by Dicumarol reduces prothrombin synthesis by the liver. As a consequence the precursor of thrombin, the precursor of autoprothrombin C, and the accessory protein of the molecular aggregate which constitutes prothrombin is reduced in concentration. It has been found possible to produce abnormal conditinos experimentally and have relatively more of the precursor of thrombin released to the blood than is normally associated with the precursor of autoprothrombin C. Up to the point of incorporation to form a single prothrombin molecule, the synthesis of subunits proceeds by separately operating mechanisms.