Coagulation serine proteases signal through protease-activated receptors (PARs). Thrombin-dependent PAR signaling on platelets is essential for the hemostatic response and vascular thrombosis, but regulation of inflammation by PAR signaling is now recognized as an important aspect of the pro- and anti-coagulant pathways. In tissue factor (TF)-dependent initiation of coagulation, factor (F) Xa is the PAR-1 or PAR-2-activating protease when associated with the transient TF-FVIIa-FXa complex. In the anticoagulant protein C (PC) pathway, the thrombin-thrombomodulin complex activates PC bound to the endothelial cell PC receptor (EPCR), which functions as a required coreceptor for activated PC-mediated signaling through endothelial cell PAR-1. Thus, the pro- and anti-inflammatory receptor cascades are mechanistically coupled to immediate cell signaling, which precedes systemic coagulant or anticoagulant effects. In contrast to the substrate-like recognition of PARs by thrombin, TF- or EPCR-targeted activation of PARs generates cell-type specificity, PAR selectivity and protease receptor cosignaling with the G-protein-coupled PAR response. Protease receptors are thus major determinants of the biological outcome of coagulation factor signaling on vascular cells.