Recent evidence suggests that protein disulfide isomerase (PDI) represents an injury response signal that can activate tissue factor (TF), a major initiator protein of blood coagulation. PDI was found to be specifically exposed at the site of vessel injury, originating both from disrupted vessel-wall cells and adhering platelets. The exposed PDI promotes TF-dependent fibrin deposition in different mouse models of thrombosis. In particular, PDI can mediate stimulation of circulating (intravascular) TF present on microparticles. It has been proposed that PDI activates TF by changing the disulfide status of the membrane-proximal Cys186-Cys209 pair of TF. Indeed, PDI was shown to cleave mixed disulfide bonds of TF with glutathione. This might enable the formation of an intrachain disulfide bond which is associated with an increased procoagulant efficiency of TF. The PDI-induced activation of TF could represent the primary step of the entire coagulation process.