IBS is a common and debilitating disorder. The pathophysiology of IBS is poorly understood and is currently viewed as a biopsychosocial disorder with symptoms mediated via the brain-gut axis. Epidemiological studies of IBS point to risk factors such as familial clustering, sexual abuse and other forms of childhood trauma, low birth weight and gastrointestinal infection. Epigenetics focuses on the complex and dynamic interaction between the DNA sequence, DNA modifications and environmental factors, all of which combine to produce the phenotype. Studies in animal models of early stress and in humans who have experienced childhood trauma or abuse suggest that these events can lead to long-lasting epigenetic changes in the glucocorticoid receptor gene brought about by hypermethylation of a key regulatory component. Animal studies also indicate that the microbiota has a pivotal role in programming the core stress system, the hypothalamic-pituitary-adrenal axis and the immune system through epigenetic mechanisms. In this Perspectives, an epigenetic model of IBS is presented that incorporates many of the current findings regarding IBS, including proinflammatory markers, neuroendocrine alterations and links with both psychosocial stress and stress related to infection. We conclude that applying epigenetic methodology to this common and disabling disorder may help unravel its complex pathophysiology and lead to more effective treatments.