Coagulation activation by the TF (tissue factor) pathway plays pivotal roles in triggering platelets and precipitating acute coronary syndromes. Although dual antiplatelet therapy is effective in secondary cardiovascular prevention, combining platelet antagonism with low-dose aspirin and the oral coagulation FXa antagonist rivaroxaban has a synergistic clinical benefit over monotherapy in preventing the composite outcome of cardiovascular death, stroke, or myocardial infarction.1 It is, therefore, of considerable interest to understand the roles of coagulation proteases and their cell signaling effects in the development of atherosclerosis and vascular inflammation. Acute thrombosis in animal models typically requires the combination of FXII contact activation and the extrinsic TF pathway,2,3 but vascular inflammation and hypertension in the absence of overt intravascular thrombosis can utilize a unique TF-initiated and platelet-assembled thrombin-FXI amplification loop independent of contact pathway FXII.4 Although atherosclerotic lesions in the mouse are typically not thrombogenic, interference with coagulation nevertheless attenuates lesion development. Genetic manipulation of thrombin generation5 or deletion of FXI,6 as well as pharmacological inhibition of FXa7 or thrombin,5 reduce atherosclerosis in ApoE (apolipoprotein E) knock-out mice, raising questions about cellular targets and proatherogenic mechanisms of coagulation proteases beyond precipitating intravascular thrombosis. See accompanying articles on pages 1271 and 1368 Two studies in the current issue of Arteriosclerosis, Thrombosis, and Vascular Biology demonstrate roles for PAR (protease-activated receptor) signaling in atherosclerosis. …