Tissue factor (TF) plays an essential role in hemostasis. The tissue-specific pattern of TF expression is consistent with additional hemostatic protection in vital organs. An aberrant expression of TF within the vasculature occurs in a variety of diseases, including atherosclerosis, cancer, and sepsis. TF expression in these diseases is associated with thrombotic events. Future therapeutic strategies may prove beneficial in the treatment of thrombosis. However, these strategies should be designed to avoid compromising hemostasis.