Since their discovery at the end of the 19(th)century, enteric glial cells (EGC), the major cellular component of the enteric nervous system, have long been considered as mere supportive cells for neurons. However, recent evidence has challenged this view and highlighted their central role in the regulation of gut homeostasis, as well as their implication in digestive and extra-digestive diseases. In this review we summarize the emerging concepts as to how EGC regulate neuromediator expression, exert neuroprotective roles and even act as neuronal as well as glial progenitors in the enteric nervous system. A particularly crucial property of EGC is their ability to maintain the integrity of the intestinal epithelial barrier, a role which may have an important clinical implications, not only for digestive diseases such as post-operative ileus and inflammatory bowel diseases, but also for extra-digestive disease, e.g. Parkinson's disease or obesity. EGC could also contribute directly to disease processes, e.g. inflammation, by their ability to secrete chemokines/cytokines in response to bacterial or inflammatory challenges. Defining the pleiotropic roles exerted by EGC may reveal a better knowledge and develop new targeted therapeutic options for a variety of gastrointestinal diseases.