Proteinase-activated receptors (PAR1 and PAR2), a family of four seven-transmembrane G protein-coupled receptors (GPCR-A15), act as targets for signaling by various proteolytic enzymes. PARs are characterized by a unique activation mechanism involving the proteolytic unmasking of a tethered ligand that stimulates the receptor. Given the broad spectrum of roles that PARs have in normal and pathological tissue function, these receptors are emerging as potential therapeutic targets for several diseases including arthritis, colitis, asthma, neurodegenerative conditions, tumor invasion and cardiovascular diseases. The proteolytic mechanisms that regulate PAR activity are more complex than initially anticipated. Thus, via a proteinase, a PAR can be: activated by a tethered ligand mechanism; disarmed for further activation by an activating proteinase; or activated via a non-canonical mechanism involving cleavage at a site distinct from the one that reveals the canonical tethered ligand sequence[1].