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Since the first description of \u201cactive\u201d transport of HCO<jats:sub>3<\/jats:sub><jats:sup>\u2212<\/jats:sup> ions against a concentration gradient in the 1970s, the fundamental role of HCO<jats:sub>3<\/jats:sub><jats:sup>\u2212<\/jats:sup> transport for multiple intestinal functions has been recognized. The ion transport proteins have been identified and molecularly characterized, and knockout mouse models have given insight into their individual role in a variety of functions. This review describes the progress made in the last decade regarding novel techniques and new findings in the molecular regulation of intestinal HCO<jats:sub>3<\/jats:sub><jats:sup>\u2212<\/jats:sup> transport in the different segments of the gut. We discuss human diseases with defects in intestinal HCO<jats:sub>3<\/jats:sub><jats:sup>\u2212<\/jats:sup> secretion and potential treatment strategies to increase luminal alkalinity. 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