Chloride Balancing Act The ionic composition of the cytosol and intracellular organelles must be regulated in the face of ongoing membrane traffic into and out of the cell. Now, two papers address the consequences of a change in the transport phenotype of an intracellular Cl ⁻ transport protein from a coupled exchanger to a passive Cl ⁻ conductor (see the Perspective by Smith and Schwappach ). Novarino et al. (p. 1398 , published online 29 April) investigated the consequence of a knock-in of the uncoupled ClC-5 transporter into mouse. The knock-out mouse of this endosomal kidney transporter has a severe endocytic phenotype believed to be due to a defect in vesicular acidification. The current study shows a similarly impaired endocytic phenotype for the uncoupled mutant, but the acidification of endosomes was unaffected. Weinert et al. (p. 1401 , published online 29 April) used a similar strategy to investigate the consequence of the equivalent mutation in the lysosomal transporter ClC-7, which is highly expressed in the resorption lacuna of osteoclasts and whose knock-out in mice produces lysosomal storage disease and severe osteopetrosis. A similar (though less severe) phenotype was observed in the knock-in mice containing the uncoupled ClC-7, indicating that coupled transport plays a critical role in lysosomes.