The linkage between activation of the coagulation system and cancer is well established, as is deregulation of tissue factor (TF) by cancer cells, their vascular stroma and cancer-associated inflammatory cells. TF is no longer perceived as an 'alternative' coagulation factor, but rather as a central trigger of the coagulation cascade and an important cell-associated signalling receptor activated by factor VIIa, and interacting with several other regulatory entities, most notably protease-activated receptors (PAR-1 and PAR-2). Preclinical studies revealed the role of oncogenic transformation and tumour micro-environment as TF regulators in cancer, along with the impact of this receptor on gene expression, tumour growth, metastasis, angiogenesis and, possibly, formation of the cancer stem cell niche. Increasing interest surrounds the shedding of TF-containing microvesicles from cancer cells, their entry into the circulation and their role in the intercellular transfer of TF activity, cancer coagulopathy and other processes. Recent data also suggest differential roles of cell autonomous versus global effects of TF in various settings. Questions are raised regarding the consequences of TF expression by tumour cells themselves and by their associated host stroma. Progress in these areas may soon begin to impact on clinical practice and, as such, raises several important questions. Can TF be exploited as a therapeutic target in cancer? Where and when may this be safe and beneficial? Is expression of TF in various disease settings useful as a biomarker of cancer progression or the associated hypercoagulability? What clinical questions related to TF are especially worthy of further exploration, at present and in the near future? Some of these developments and questions will be discussed in this chapter.