TFPI-2, tissue factor pathway inhibitor 2, is a member of the Kunitz-type serine proteinase inhibitor family. This protein contains three Kunitz domains that are flanked by less structured peptide segments. It also contains a highly negatively charged N-terminus and a highly positively charged C-terminus. It has been shown that the first Kunitz domain, K1, inhibits the tissue factor (TF)-VIIa complex, while the K2 domain inhibits factor Xa. A direct protease that inhibits functions for the K3 domain has not been identified. When TFPI forms a complex with factor Xa, it becomes a much more potent inhibitor for VIIa-TF than by itself. TFPI-2 strongly prevents extracellular matrix (ECM) degradation by inhibiting plasmin and matrix metalloproteinases (MMPs). Recent studies show that TFPI-2 is down-regulated in several invasive tumor cell lines, which include glioma, prostate cancer, melanoma, fibrosarcoma, breast cancer, and pancreatic ductal adenocarcinoma. The expression of TFPI-2 in cancer cells can inhibit tumor cell growth and metastasis in vivo by modulating ECM remodeling and angiogenesis. Importantly, the aberrant methylation of TFPI-2 gene promoters is associated with malignant tumors. Thus, TFPI-2 might be involved in tumor progression and this protein's expression might have a prognostic value in cancer patients. Additionally, it has been shown that the highly positively charged C-terminus posseses antibacterial activity and is cleavaged by ADAMTS1, plasmin, and thrombin.