Activation of coagulation precedes or coincides with angiogenesis in wound healing and postischemic tissue regeneration. Advanced cancer is associated with a hypercoagulable state, and tissue factor expression by cancer cells has received widespread attention because of its significant contribution to the pathogenesis of cancer progression and metastasis. Our recent work demonstrates that tissue factor–mediated cellular signaling is relevant to cancer angiogenesis. Here we review the molecular mechanisms of tissue factor pathways in angiogenesis and tumorigenesis with emphasis on the intriguing role for tissue factor cytoplasmic domain signaling.