Background The transport of transepithelial Cl- and HCO3- is crucial for the function of the intestinal epithelium and maintains the acid-based homeostasis. Slc26a3 (DRA), as a key chloride-bicarbonate exchanger protein in the intestinal epithelial luminal membrane, participates in the electroneutral NaCl absorption of intestine, together with Na+/H+ exchangers. Increasing recent evidence supports the essential role of decreased DRA function or expression in infectious diarrhea and inflammatory bowel disease (IBD). Method In this review, we give an overview of the current knowledge of Slc26a3, including its cloning and expression, function, roles in infectious diarrhea and IBD, and mechanisms of actions. A better understanding of the physiological and pathophysiological relevance of Slc26a3 in infectious diarrhea and IBD may reveal novel targets for future therapy. Conclusion Understanding the physiological function, regulatory interactions, and the potential mechanisms of Slc26a3 in the pathophysiology of infectious diarrhea and IBD will define novel therapeutic approaches in future.