Blood coagulation is essential for life. The clotting cascade is divided into extrinsic (tissue factor and factor VIIa), intrinsic (factors XIIa, XIa, IXa, and FVIIIa), and common (factor Xa, factor Va, and thrombin) pathways that generate cross-linked fibrin. Hemostasis is a physiological process that prevents excess bleeding after vessel injury. Under normal conditions, all coagulation factors, except tissue factor, reside in the blood. Tissue factor is expressed in the vessel wall and activates the clotting system after injury. Thrombosis is a pathological process that leads to occlusion of blood vessels. Thrombosis can be triggered by rupture of an atherosclerotic plaque or by tissue factor–positive microparticles in the blood. Mice lacking components of the extrinsic or common pathways do not survive, which indicates that these pathways are essential for hemostasis. In contrast, mice lacking either factor XI or factor XII have no hemostatic defects, which suggests that these factors are not required for hemostasis. Mice deficient in either factor VIII or IX survive but exsanguinate after tail transection, consistent with a role in amplification of the cascade. Surprisingly, mice lacking either factor XII or factor XI were protected in thrombosis models demonstrating a role in thrombosis. These results reveal mechanistic differences between hemostasis and thrombosis. At present, the identity of the activators of the intrinsic pathway has not been defined but may include extracellular RNA released from damaged cells and polyphosphate secreted from activated platelets. A better understanding of the different pathways may lead to the development of novel antithrombotic drugs. These designations were based on the “ex vivo” activation of coagulation. An “extrinsic” factor called tissue thromboplastin (also known as factor III or tissue factor) initiated clotting via the extrinsic pathway, and this reaction formed the basis of the prothrombin time assay. In contrast, addition of blood to a negatively charged surface, such as kaolin, activated the clotting cascade via the intrinsic pathway. This is called the activated partial thromboplastin time and is driven by factor XIIa (also known as Hageman factor). However, individuals deficient in factor XII, such as John Hageman, were not bleeders. This suggested that factor XIIa was not required for in vivo clotting. In 1991, Gailani and Broze found that thrombin could activate factor XI and factor XII was largely removed from diagrams of the clotting cascade. Studies on mice lacking different clotting factors demonstrated essential roles in hemostasis for components of the extrinsic and common pathways.