The pathogenesis of irritable bowel syndrome (IBS) has traditionally been based on the biopsychosocial model that emphasizes that the symptom manifestations of IBS and consulting behavior are influenced at least in part by psychological processes. However, there has been increasing interest in trying to identify and unravel potential molecular mechanisms in IBS, and this endeavor has been driven by some evidence that there is a true genetic contribution to IBS. IBS does aggregate in families, and the concordance of IBS is twice as great in monozygotic compared with dizygotic twins in most, but not all, studies. A number of genetic polymorphisms have been associated with IBS but most remain to be independently confirmed, and unknown gene-environment interactions probably remain essential for the disorder to manifest. As we become better able to specify the phenotypes within IBS, it seems likely that increasingly relevant gene associations that have implications for testing and treatment will rapidly be identified. IBS probably represents a collection of several organic diseases, some of which may have a genetic component; the biopsychosocial model, although important, may represent a gross oversimplification of the underlying molecular pathogenesis.