Proteinase-activated receptors (PARs), a family of G protein-coupled receptors consisting of four members, are now known to mediate cellular actions of several proteinases in the mammalian body. In the gastrointestinal (GI) tract, PARs, particularly PAR1, a receptor for thrombin, and PAR2, a receptor activated by trypsin, tryptase, etc., are widely distributed, modulating various functions in health and disease. One of the major functions of PARs in the GI systems is to regulate glandular exocrine secretion. PAR2-activating peptides cause prompt salivation in laboratory animals, an effect disappearing in PAR2-deficient animals. Since PAR2-related peptides also trigger tear secretion through PAR2 and non-PAR2 mechanisms, PAR2 could be a therapeutic target for treatment of secretion disorders. Activation of PAR2 also stimulates exocrine secretion of pancreatic juice and enzymes in vivo as well as in vitro. In the gastric mucosa, PAR2-activating peptides trigger secretion of mucus via excitation of capsaicin-sensitive sensory neurons (Kawabata A et al. 2001) and secretion of pepsinogen by chief cells, but suppress acid secretion. Regulation of intestinal ion transport by PAR2 and PAR1 has also been well described. Thus, PARs, particularly PAR2, appear to play critical roles in regulation of exocrine secretion. Regulation of smooth muscle tone by PAR1, PAR2 and PAR4 has also been well documented in the esophageal, gastric and intestinal tissues. The roles played by PARs in GI diseases are a little complicated. We have shown that PAR2 agonists protect against gastric mucosal injury through stimulation of sensory neurons (Kawabata A et al. 2001), while PAR1 agonists exert gastric mucosal protection through stimulation of prostanoid formation (Kawabata A et al. 2004). In a rat normal gastric epithelial cell line, PAR1 stimulation activates multiple signaling pathways, leading to delayed formation of prostaglandin E2 (Sekiguchi F et al. 2007. Both anti- and pro-inflammatory roles for endogenous proteinases and/or PAR1/PAR2 have been demonstrated in distinct animal models for colitis. Most interestingly, PAR2 present in the sensory neurons or epithelial cells appears to participate in the pathogenesis of irritable bowel syndrome (IBS). Some studies have emphasized the benefit of therapeutic use of proteinase inhibitors and antagonists of PAR2 or PAR1 for treatment of the gastroesophageal reflux disease, inflammatory bowel disease, IBS, etc. In the pancreas, PAR2 is expressed by both sensory neurons and acinar cells. Stimulation of PAR2 in the sensory neurons causes pancreatic pain, and inhibitors of PAR2-activating proteinases can reverse the referred pain accompanying the established pancreatitis. In contrast, at the early stage of pancreatitis, PAR2 present in the acinar cells might mediate secretion of pancreatic proteinases into the duodenal lumen followed by decreased content of proteinases in the pancreas, leading to protection against the development of pancreatitis and related pain (Kawabata A et al. 2006; Singh VP et al. 2007). PAR2 is thus considered pro-inflammatory/nociceptive and also protective/antinociceptive. Taken together, it is no doubt that activation of PARs, particularly PAR2 and PAR1, plays critical roles in the GI tract in health and disease, regardless of favorable/unfavorable outcomes.