Proteinases like thrombin, trypsin and tissue kallikreins are now known to regulate cell signaling by cleaving and activating a novel family of G-protein-coupled Proteinase-activated Receptors (PARs 1 to 4) via exposure of a tethered receptor-triggering ligand (Pharmacol. Rev. 54:203, 2002). On their own, short synthetic PAR-selective PAR-activating peptides mimicking the tethered ligand sequences (PAR-APs) can activate PARs 1, 2 and 4 and cause physiological responses both in vitro and in vivo. Using the PAR-APs as probes in vivo, it has been found that PAR activation can affect the vascular, renal, respiratory, gastrointestinal, musculoskeletal and nervous systems (both CNS & PNS) and can promote cancer metastasis and invasion. In general, responses triggered by PARs 1, 2 and 4 are in keeping with an innate immune inflammatory response, ranging from vasodilatation to intestinal inflammation, increased cytokine production and increased nociception. Further, PARs have been implicated in a number of disease states including cancer and inflammation of the cardiovascular, respiratory, musculoskeletal, gastrointestinal and nervous systems. In addition to activating PARs, proteinases can cause hormone-like effects by other signaling mechanisms that may be as important as the activation of PARs. Thus, the working hypothesis of the presentation will be that the PARs themselves, their activating serine proteinases or their associated signaling pathways can be considered as attractive targets for therapeutic drug development; and that proteinases in general must now be considered as ‘hormone-like’ messengers that can signal either via PARs or other mechanisms.