The onset of pendrin expression during development of the mouse inner ear has been determined to be embryonic day (ED) 13 [14]. Morphologically detectable differences in the inner ears of Slc26a4+/+ and Slc26a4-/- mice become evident as early as ED 15, when Slc26a4-/- mice start to develop an enlarged endolymphatic space that persists into adulthood [14]. Interestingly, sensory hair cells in the cochlea appear normal until postnatal day (PD) 7 but show clear evidence of degeneration by PD 15 [14]. These observations suggest that the cochlear environment supports the survival of sensory hair cells in spite of the enlargement of the endolymphatic duct. A normal endolymphatic K+ concentration, which is critical for hair cell survival [20], is established at PD 3 [21] and may persist in Slc26a4-/- at least until PD 7. The time period between PD 7 and 15 is the time when the endocochlear potential develops at the onset of hearing [22]. We hypothesized that a lack of a normal endocochlear potential or an alteration of the endolymphatic K+ concentration could account for deafness in Slc26a4-/- mice. Measurements revealed that the endocochlear potential was absent but that the endolymphatic K+ concentration was normal in adult Slc26a4-/- (Fig. 2a). No significant differences between Slc26a4+/+ and Slc26a4-/- mice were found in perilymphatic (Fig. 2a) or plasma K+ concentrations (Slc26a4+/+, 4.9 ± 0.3 mM, n = 6; Slc26a4-/-, 5.1 ± 0.3 mM, n = 6). These observations suggest that a primary event leading to deafness in Slc26a4-/- mice, and potentially in patients suffering from Pendred syndrome, is the loss of the endocochlear potential. Degeneration of hair cells is probably a response to the loss of the endocochlear potential.