Since their discovery at the end of the 19th century, enteric glial cells (EGCs), the major cellular component of the enteric nervous system, have long been considered 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 extradigestive diseases. In this review, we summarize emerging concepts as to how EGCs 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 EGCs is their ability to maintain the integrity of the intestinal epithelial barrier, a role that may have important clinical implications not only for digestive diseases, such as postoperative ileus and inflammatory bowel diseases, but also for extradigestive diseases, such as Parkinson disease or obesity. EGCs could also contribute directly to disease processes (eg, inflammation) by their ability to secrete chemokines/cytokines in response to bacterial or inflammatory challenges. Defining the pleiotropic roles exerted by EGCs may reveal better knowledge and help develop new targeted therapeutic options for a variety of gastrointestinal diseases.