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Idiopathic thrombosis often precedes the diagnosis of occult cancer by several years. Whether hypercoagulability predisposes for malignancy or the converse holds true is an unresolved paradigm that stems from the known vicious cycle of clot formation and tumor growth. Central to this paradigm is the interplay between tissue factor (TF), the initiator of coagulation, and angiogenesis, the life support of tumors. Both clotting-dependent and -independent mechanisms of TF-induced angiogenesis have been elucidated that may signal through distinct pathways. This review focuses on the latest studies of TF and angiogenesis and highlights recent applications that have led to the development of promising new TF-targeted cancer therapeutics. Finally a cautionary note is given about unexpected complications arising from antiangiogenic therapy that may potentially involve TF.