The duodenum serves as a buffer zone between the stomach and jejunum. Over a length of only 25 cm, large volumes of strong acid secreted by the stomach must be converted to the neutral-alkaline chyme of the hindgut lumen, generating large volumes of CO₂, which the duodenum then absorbs. The duodenal mucosa consists of epithelial cells connected by low-resistance tight junctions, forming a leaky epithelial barrier. Despite this high permeability, the epithelial cells, under intense stress from luminal mineral acid and highly elevated Pco₂, maintain normal functioning. Furthermore, the duodenum plays an active role in foregut acid-base homeostasis, absorbing large amounts of H⁺ and CO₂ that are recycled by the gastric parietal cells. Prompted by the high expression of cytosolic and membrane carbonic anhydrase (CAs) in duodenal epithelial cells, and the intriguing observation that CA activity appears to augment cellular acid stress, we formulated a novel hypothesis regarding the role of CA in duodenal acid absorption, epithelial protection, and chemosensing. In this review, we will describe how luminal CO₂/H⁺ traverses the duodenal epithelial cell brush border membrane, acidifies the cytoplasm, and is sensed in the subepithelium.