Histopathologic data demonstrate low-grade mucosal inflammation in a subset of patients with irritable bowel syndrome (IBS). This inflammatory infiltrate is mainly represented by increased numbers of T lymphocytes and mast cells lying in the lamina propria. The close apposition of immunocytes to gut nerves supplying the mucosa provides a basis for neuroimmune cross-talk, which may explain gut sensorimotor dysfunction and related symptoms in patients with IBS. A previous gastroenteritis (due to Campylobacter jejuni, Salmonella, Shigella, Escherichia coli, and, likely, viruses) is now an established etiologic factor for IBS (hence, postinfectious IBS). Other putative causes, such as undiagnosed food allergies, genetic abnormalities, stress, or bile acid malabsorption, may also promote and maintain a low-grade mucosal inflammation in IBS. The identification of mucosal inflammation in IBS has pathophysiologic implications and paves the way for novel therapeutic options.