During lysosomal acidification, proton-pump currents are thought to be shunted by a chloride ion (Cl–) channel, tentatively identified as ClC-7. Surprisingly, recent data suggest that ClC-7 instead mediates Cl–/proton (H+) exchange. We generated mice carrying a point mutation converting ClC-7 into an uncoupled (unc) Cl– conductor. Despite maintaining lysosomal conductance and normal lysosomal pH, these Clcn7unc/unc mice showed lysosomal storage disease like mice lacking ClC-7. However, their osteopetrosis was milder, and they lacked a coat color phenotype. Thus, only some roles of ClC-7 Cl–/H+ exchange can be taken over by a Cl– conductance. This conductance was even deleterious in Clcn7+/unc mice. Clcn7–/– and Clcn7unc/unc mice accumulated less Cl– in lysosomes than did wild-type mice. Thus, lowered lysosomal chloride may underlie their common phenotypes.