The plasma coagulation system reacts quickly to limit blood loss from injury sites but also contributes to vascular thrombosis. In current models of hemostatic balance, normal coagulation and thrombosis represent two sides of the same coin, however, recent data from gene-deleted murine models have challenged this dogma. Deficiency of coagulation Factor XII (Hageman factor), a serine protease that initiates the intrinsic pathway of coagulation, severely impairs arterial thrombus formation but is not associated with excessive bleeding. These findings suggest that fibrin-generating mechanisms that operate during pathologic thrombus formation involve pathways distinct from those that are active during normal hemostasis. As Factor XII selectively contributes to thrombus formation in occlusive disease, but not to normal hemostasis, inhibition of this protease may offer a novel treatment strategy for prevention of arterial thrombosis with minimal or no risk of bleeding.