The study of intestinal electrolyte transport is a fairly old discipline, with very important mechanistic insight into the regulation of gastric acid and duodenal bicarbonate secretion, small intestinal and distal colonic Na⁺ absorption having been made in the seventies and eighties of the last century. The cloning and characterization of a multitude of transport protein has provided molecular insight into many of the transport processes delineated decades earlier. Recent data have provided novel mechanistic insight how the CFTR chloride channel may become permeable for HCO₃- through the activation of the WNK (with no lysine)-kinases signalling pathway, which may explain the strong CFTR-dependent HCO₃^- secretory rate of duodenal villous epithelium. In contrast, colonic surface HCO3- secretion is dominated by the action of the Cl^-/HCO₃^- exchanger Slc26a3 (DRA), while CFTR mediates Cl^- and fluid secretion from the crypts. The strong small intestinal expression of the Slc26a6 isoform (PAT-1) may be related to its ability to absorb HCO₃^- during CO₂ or nutrient- mediated enterocyte acidification. Lastly, novel data provide insight into the question why a defect in a number of intestinal ion transporters, such as CFTR, the Na⁺/H⁺ exchanger isoform NHE3, or the Cl^-/HCO₃^- exchanger isoform Slc26a3 (DRA) result in a propensity for colonic inflammation and how the function of electrolyte transporters regulate the proper buildup of a colonic mucus layer.