Mutations in the gene encoding for the K⁺ channel α-subunit KCNQ1 have been associated with long QT syndrome and deafness. Besides heart and inner ear epithelial cells, KCNQ1 is expressed in a variety of epithelial cells including renal proximal tubule and gastrointestinal tract epithelial cells. At these sites, cellular K⁺ ions exit through KCNQ1 channel complexes, which may serve to recycle K⁺ or to maintain cell membrane potential and thus the driving force for electrogenic transepithelial transport, e.g., Na⁺/glucose cotransport. Employing pharmacologic inhibition and gene knockout, the present study demonstrates the importance of KCNQ1 K⁺ channel complexes for the maintenance of the driving force for proximal tubular and intestinal Na⁺ absorption, gastric acid secretion, and cAMP-induced jejunal Cl^- secretion. In the kidney, KCNQ1 appears dispensable under basal conditions because of limited substrate delivery for electrogenic Na⁺ reabsorption to KCNQ1-expressing mid to late proximal tubule. During conditions of increased substrate load, however, luminal KCNQ1 serves to repolarize the proximal tubule and stabilize the driving force for Na⁺ reabsorption. In mice lacking functional KCNQ1, impaired intestinal absorption is associated with reduced serum vitamin B12 concentrations, mild macrocytic anemia, and fecal loss of Na⁺ and K⁺, the latter affecting K⁺ homeostasis.