The duodenum is the first segment of the small intestine, just distal to the gastric pylorus. This positions the epithelial lining of the duodenum directly in the path of destructive gastric acid leaving the stomach. Because pancreatic bicarbonate secretions only enter the gut lumen farther down the gastrointestinal tract, the early duodenum must defend itself, unaided, from this acidic stress. The duodenal defenses can be conveniently grouped as pre-epithelial (e.g., neutralization of acid in the lumen), epithelial (e.g., tight junctions, membrane impermeability to acid, secretion of alkali and mucus), and subepithelial (e.g., afferent and efferent neural mechanisms, blood flow). Each of these contributions to mucosal defense is potentially important to human health because acid damage is a crucial aggravating factor in formation and persistence of duodenal ulcers (1). In terms of duodenal defense, strong interest has centered on the avid bicarbonate secretion mediated by duodenal epithelial cells. This is unequivocally the first line of defense, as the bicarbonate reaching the gut lumen will act to neutralize intraluminal acid (producing CO2 and water) before it ever reaches the cells. Elegant and rigorous experiments have shown that, as a consequence of this neutralization, the spaces directly adjacent to the epithelium have close to a neutral pH (2, 3). This juxtamucosal alkaline layer also contributes to mucosal defense by directly shielding duodenal epithelial cells from luminal acid. The article by Akiba et al. in this issue of the JCI (4) is interesting and important because it raises a new possibility: that bicarbonate secretory mechanisms may have an even greater role in acid defense through their effects on intracellular pH of duodenal epithelial cells. The central observation reported by Akiba et al. is that two anion transport inhibitors (DIDS and NPPB) both block bicarbonate secretion into the lumen but that these agents have opposite effects on cellular damage in response to luminal acid (4). Most strikingly, NPPB actually reduces the damage in response to luminal acid. These results are not readily compatible with conventional models of extracellular defense, since inhibition of bicarbonate secretion will compromise both luminal neutralization of acid and the juxtamucosal alkaline layer. Despite uncertainty about the molecular specificity of the drugs, these new in vivo results clearly demonstrate a dissociation between bicarbonate secretion and cytoprotection.