The coagulation cascade and protease-activated receptors (PARs) together provide an elegant mechanism that links mechanical information in the form of tissue injury to cellular responses. These receptors appear to largely account for the cellular effects of thrombin and can mediate signaling to other trypsin-like proteases. An important role for PARs in hemostasis and thrombosis is established in animal models, and studies in knockout mice and nonhuman primates raise the question of whether PAR inhibition might offer an appealing new approach to the prevention and treatment of thrombosis. PARs may also trigger inflammatory responses to tissue injury. For example, PAR activation on endothelial cells and perhaps sensory afferents can trigger local accumulation of leukocytes and platelets and transudation of plasma. However, panoply of signaling systems and cell types orchestrates inflammatory responses, and efforts to define the relative importance and roles of PARs in various inflammatory processes are just beginning. Lastly, roles for PARs in blood vessel formation and other processes during embryonic development are emerging, and whether these reflect new roles for the coagulation cascade and/or PAR signaling to other proteases remains to be explored.