Irritable bowel syndrome (IBS) is characterized by chronic abdominal pain or discomfort and altered gastrointestinal function of unknown etiology. Studies of colonic mucosal biopsies from patients with IBS have suggested altered immune system function as a potential mechanism in the pathophysiology of IBS, but efforts to identify the mucosal mediators responsible for the manifestation of symptoms that define the disorder have been limited. In this issue of Neurogastroenterology and Motility, Buhner et al. and Balestra et al. report findings from studies linking increased excitability of the enteric nervous system with mucosal mediators released from biopsies of patients with IBS. These studies provide evidence for the concept that mediators present in the colonic mucosa may contribute to the manifestation of clinical symptoms present in IBS.