Tissue factor (TF), the primary cellular initiator of blood coagulation, is also involved in cancer-related processes such as hypercoagulability (Trousseau syndrome), tumor growth, angiogenesis, and metastasis. Indeed, elevated TF expression by cancer cells and their associated endothelial cells has been reported frequently. Oncogenic events in cancer cells (e.g., expression of mutant K- ras, EGFR, PTEN or p53) lead to an increase in TF levels and activity, and thereby promote tumor aggressiveness, angiogenesis, and hypercoagulability. Like TF, thrombin receptor (protease-activated receptor-1) is also upregulated in cancer cells expressing oncogenic K -ras. Pharmacological antagonists of some of these transforming genes (e.g., epidermal growth factor receptor inhibitors) could diminish TF expression, both locally and systemically, and hence these targeted agents could be viewed as potential indirect and cancer-specific anticoagulants, in addition to their direct antitumor effects. We postulate that levels of circulating TF may be useful in monitoring the biological activity of these agents. Although TF is essential for vascular development, its expression by tumor-associated endothelium appears to play a subtle and seemingly dispensable role. Thus, TF is a pivotal element of the tumor-vascular interface, is involved in many cancer-related processes, and may well constitute a promising new target for anticancer combination therapies in some disease settings.