Most G protein-coupled receptors (GPCRs) are reversibly activated upon ligand binding. However, activation of protease-activated G protein-coupled receptors (PARs) occurs through an irreversible proteolytic event that results in the generation of a tethered ligand that cannot diffuse away. This unusual mode of PAR activation raises important questions regarding the mechanisms responsible for termination of receptor signaling. There are currently four members of the PAR family. Thrombin activates PAR1, PAR3, and PAR4, whereas multiple trypsin-like serine proteases activate PAR2. The regulation of signaling by PAR1 has been extensively studied, whereas considerably less is known about the other PARs. It has been demonstrated that rapid termination of PAR1 signaling is critical in determining the magnitude and kinetics of the cellular protease response. Therefore, elucidating the molecular mechanisms involved in the regulation of PAR signaling is essential to fully understand protease-mediated responses. Recent findings indicate that novel mechanisms contribute to PAR1 desensitization, internalization, and down-regulation. This review focuses on the intracellular mechanisms that regulate PAR signaling and the recent progress in developing inhibitors of PAR signaling.