Hemostasis depends on a large number of interdependent processes to prevent spontaneous bleeding and to stop hemorrhage when vascular injury occurs. Although it is commonly divided into primary and secondary for the purpose of simplification and patient evaluation, both processes occur almost simultaneously in vivo. The goal of secondary hemostasis is to produce a firm, cross-linked fibrin clot to stabilize the platelet plug. Fibrin is generated from a series of enzymatic reactions that comprise the coagulation cascade. In this review, we describe the background, physiology, diagnosis, and treatment of congenital and acquired coagulation factor deficiencies. For each condition, we discuss the appropriate laboratory assays as well as the most current treatment modalities. In addition, we describe in detail the oral and parenteral anticoagulants currently available in the United States, their mechanism of action, laboratory monitoring (if appropriate), and how to reverse their effect in case of hemorrhage or need for an emergent procedure. Finally, we review the effect of systemic conditions such as liver disease and disseminated intravascular coagulation (DIC) on the coagulation cascade.