The recent detection of protease-activated receptors (PARs) on neurons of the peripheral and central nervous systems suggests that PARs and proteases that activate them, might be involved in neuronal functions. Among those functions, a particular focus on nociception has attracted considerable interest. The present article summarizes recent research progress on proteases and PARs as nociceptive signaling molecules in the nervous system and presents them as exciting new targets for therapeutic intervention in pain.