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Gap junctions, which mediate intercellular communication, are key players in digestive homeostasis. They are also frequently involved in gastrointestinal and liver pathology. This equally holds true for connexin (Cx) hemichannels, the structural precursors of gap junctions, and pannexin (Panx) channels, Cx-like proteins assembled in a hemichannel configuration. Both Cx hemichannels and Panx channels facilitate extracellular communication and drive a number of deteriorative processes, such as cell death and inflammation. Cxs, Panxs, and their channels underlie a wide spectrum of gastrointestinal and liver diseases, including gastritis and peptic ulcer disease, inflammatory intestinal conditions, acute liver failure, cholestasis, hepatitis and steatosis, liver fibrosis and cirrhosis, infectious gastrointestinal pathologies, and gastrointestinal and liver cancer. This could open promising perspectives for the characterization of new targets and biomarkers for therapeutic and diagnostic clinical purposes in the area of gastroenterology and hepatology.