Tissue factor pathway of coagulation plays a dominant role during normal haemostasis. Tissue factor pathway inhibitor (TFPI), expressed primarily by the microvascular endothelium, appears to be the major physiologic inhibitor of TF-induced coagulation. TF-initiated coagulation also plays an important role in the pathophysiology of many diseases including coronary thrombosis, sepsis, disseminated intravascular coagulation, stroke, cancer, acute respiratory distress syndrome, and ischemia-reperfusion injury. Several animal studies have found a beneficial effect of anti-TF monoclonal antibodies and, recombinant TFPI in some of the above clinical conditions. rTFPI is presently being used in clinical trials in patients with sepsis and in those following microvascular surgery. This article discusses many of the animal studies addressing inhibition of TF-induced coagulation, as well as potential therapeutic uses of rTFPI in humans.