Tissue factor (TF) plays a crucial role in the pathogenesis of thrombotic, vascular, and inflammatory disorders, and thus, the inhibition of this membrane protein provides a unique therapeutic approach for prophylaxis and/or treatment of various diseases. In recent years, tissue-factor pathway inhibitor (TFPI), the only endogenous inhibitor of the TF/FVIIa complex, has been characterized biochemically and pharmacologically. Studies in patients have demonstrated that both TF and TFPI may be indicators for the course and the outcome of cardiovascular and other diseases. Based on experimental and clinical data, TFPI may become an important drug for several clinical indications. TFPI is expected to inhibit the development of postinjury intimal hyperplasia and thrombotic occlusion in atherosclerotic vessels, and to be effective in acute coronary syndromes (ACS) such as unstable angina (UA) and myocardial infarction (MI). Of special interest is the inhibition of TF-mediated processes in sepsis and disseminated intravascular coagulation, which are associated with the activation of various inflammatory pathways as well as the coagulation system. A phase II trial of the efficacy of TFPI in patients with severe sepsis showed a mortality reduction in TFPI- compared to placebo-treated patients and an improvement of organ dysfunctions. TFPI can be administered exogenously in high doses to suppress TF-mediated effects, or high amounts of TFPI can be released from intravascular stores by other drugs such as heparin and low molecular weight heparins (LMWHs).