Substantial epidemiologic, laboratory, pathologic and clinical evidence supports the historic association between activation of blood coagulation and progression of cancer. The increased risk for venous thromboembolism(VTE) in cancer has been considered an epiphenomenon. However, recent studies from several laboratories have linked more closely malignanttransformation (oncogenesis), tumor angiogenesis and metastasis to the generation of clotting intermediates(e.g. tissue factor [TF], factor Xa and thrombin),clotting or platelet function inhibitors (e.g. COX-2) or fibrinolysis inhibitors (e.g. plasminogen activator inhibitor, type 1 [PAI-1]). Furthermore, TF, Xa and thrombin may induce important tumor cell signaling cascades in a clotting-dependent and/or clotting independent manner (e.g. thru engagement of protease-activated receptors [PARs]). Targeting blood clotting reactions in cancer may provide a unique approach to cancer treatment.