Hemostasis is a natural process that stops bleeding when blood vessels are injured. It is a complex defense mechanism that maintains the integrity of blood vessels. Normal hemostasis relies on the interaction of blood vessels, platelets, coagulation factors, and the fibrinolytic system. The traditional coagulation cascade model, which includes intrinsic and extrinsic pathways, has been extensively revised. The cell-based model of coagulation is now widely accepted as the most accurate representation of the process in vivo. This model also offers a clearer explanation of cellular and enzymatic hemostatic reactions, as well as hemostatic disorders. According to a more recent approach or concept, the coagulation process is divided into three distinct phases: (1) an initiation phase where a small amount of coagulation factors is activated, (2) an amplification phase in which, through amplification loops in the coagulation cascade, large amounts of fibrin are produced, and (3) a propagation phase in which coagulation factors are concentrated on phospholipids exposed on the platelet surface, leading to the formation of stable fibrin meshes. Antithrombin III, tissue factor pathway inhibitors, and protein C play major roles in regulating blood coagulation. In this chapter, both the cascade and cell-based models of coagulation are presented, along with an overview of coagulation factors and natural anticoagulants.