Protease-activated receptors (PARs) are G protein-coupled receptors (GPCRs) that transmit cellular responses begun by the actions of extracellular proteases. The activation of a PAR occurs by a unique mechanism whereby the extracellular N-terminal segment of the inactive receptor undergoes proteolytic cleavage, resulting in irreversible activation--unlike most GPCRs that are reversibly activated. PARs mediate cellular responses to coagulant proteases in various cell types localized within the vasculature. Additionally, PARs are expressed in other cell types and respond to a plethora of proteases. Recent studies have revealed that different proteases elicit distinct responses through the activation of the same PAR. This phenomenon appears to involve stabilization of distinct active PAR conformations that facilitates selectively coupling to different effectors and is localized to caveolae, a subtype of lipid rafts.