Abstract Knowledge of neural circuits, neurotransmitters and receptors involved in the sympathetic regulation of gastrointestinal (GI) function is well established. However, it is only recently that the interaction of sympathetic neurons, and of sympathetic transmitters, with the GI immune system and with gut flora has begun to be explored. Changes in the behaviour of sympathetic nerves when gut function is compromised, for example in ileus and in inflammation, have been observed, but the roles of the sympathetic innervation in these and other pathologies are not adequately understood. In this article, we first review the principal roles of the sympathetic innervation of the GI tract in controlling motility, fluid exchange and gut blood flow in healthy individuals. We then discuss the evidence that there are important interactions of sympathetic transmitters with the gut immune system and enteric glia, and evidence that inflammation has substantial effects on sympathetic neurons. These reciprocal interactions contribute to pathological changes in ways that are not yet clarified. Finally, we focus on inflammation, diabetes and postoperative ileus as conditions in which there is sympathetic involvement in compromised gut function.