Regulation of pH is necessary to the production of an environment conducive to enamel growth and mineralization. We hypothesize that abnormal extracellular pH in the enamel matrix of mice with the cystic fibrosis gene knocked out (CF mice) results in altered enamel mineralization. The enamel matrix pH during amelogenesis was studied in 10 normal and 10 CF mice. Freshly dissected incisors were immersed in pH indicator or glyoxal bis (2-hydro-xyanil) (GBHA). The normal mouse enamel matrix pH was generally higher and modulated differently than did the CF mouse enamel. GBHA staining showed that normal mice had 2 well-demarcated bands in the maturation zone that correlated to the neutral pH zones, while CF mice showed no staining. These results indicate that CFTR plays a role in pH regulation during enamel development and that a reduced pH results in a lack of calcium influx during enamel maturation and hypomineralization of the CF incisor enamel.