In cystic fibrosis, the loss-of-function of CFTR, a membrane protein that allows apical efflux of Cl- from secretory epithelial cells, causes the mucus obstruction characteristic of the disease. The Cl- channel CIC-2 might function as an alternative route for Cl- efflux that, if pharmacologically activated, would compensate for CFTR deficiency, but its cellular localization is controversial. On p. 4243, Francisco Sepúlveda and co-workers use immunocytochemistry to show that CIC-2 localizes exclusively to the basolateral membranes of absorptive intestinal epithelial cells in vivo. Then, in transfection assays, they demonstrate that CIC-2 sorts to the basolateral membrane of several epithelial cell lines; this sorting is dependent on the AP-1B clathrin adaptor complex and on a di-leucine motif in a C-terminal crystathione beta synthase domain (CBS-2) of CIC-2. Drugs that modulate the function of the CBS-2 domain might therefore allow CIC-2 to compensate for loss of CFTR in cystic fibrosis by altering its targeting.