Recent studies have provided evidence to suggest a possible role for mucosal immune activation in the pathophysiology of irritable bowel syndrome (IBS). On the other hand, novel findings using functional brain-imaging techniques support the concept that altered perception of visceral stimuli plays a key role in IBS symptom generation. These seemingly contradictory findings have revived the discussion about the relative contribution of peripheral versus central mechanisms in the symptom generation of IBS. In this review, we will provide evidence for the hypothesis that, in the absence of changes in visceral perception and alterations in endogenous pain modulation systems, chronic inflammatory mucosal changes in the gut are not a plausible mechanism to explain the presence of chronic abdominal pain, a clinical hallmark of IBS.