Emerging evidence shows a broad spectrum of biological functions of tissue factor (TF). TF classical role in initiating the extrinsic blood coagulation and its direct thrombotic action in close relation to cardiovascular risks have long been established. TF overexpression/hypercoagulability often observed in many clinical conditions certainly expands its role in proinflammation, diabetes, obesity, cardiovascular diseases, angiogenesis, tumor metastasis, wound repairs, embryonic development, cell adhesion/migration, innate immunity, infection, pregnancy loss, and many others. This paper broadly covers seminal observations to discuss TF pathogenic roles in relation to diverse disease development or manifestation. Biochemically, extracellular TF signaling interfaced through protease-activated receptors (PARs) elicits cellular activation and inflammatory responses. TF diverse biological roles are associated with either coagulation-dependent or noncoagulation-mediated actions. Apparently, TF hypercoagulability refuels a coagulation-inflammation-thrombosis circuit in "autocrine" or "paracrine" fashions, which triggers a wide spectrum of pathophysiology. Accordingly, TF suppression, anticoagulation, PAR blockade, or general anti-inflammation offers an array of therapeutical benefits for easing diverse pathological conditions.