Guanylate Cyclase C (GCC) is expressed almost exclusively in the intestinal epithelium of the small and large intestine on the luminal surface. The activity of this receptor is regulated by the endogenous hormones, guanylin and uroguanylin which are secreted into the intestinal lumen and then act locally to activate the GCC receptor. Our goal has been to develop an understanding of the utility of guanylate cyclase agonists for the treatment of intestinal diseases, including irritable bowel sydrome with constipation (IBS-C) and chronic constipation (CC). These two conditions affect millions of patients and are associated with marked pain and discomfort. In the current talk, we will focus on the actions of linaclotide, a synthetic 14-amino acid peptide GCC agonist that is marketed in multiple countries, on animal models of abdominal pain and intestinal transit and the relationship of these actions for the treatment of intestinal dysfunction in IBS-C and CC patients by examining the effect of linaclotide treatment on the abdominal symptoms associated with IBS-C, including abdominal pain. In our clinical studies, we have explored acute release and delayed release formulations with a goal of targeting specific pharmacologic actions to the small or large intestine.