In normal conditions, filtered albumin and low-molecular-weight (LMW) proteins are almost entirely reabsorbed by apical receptor-mediated endocytosis in the proximal tubule (PT) cells of the kidney. The chloride transporters ClC-5 and CFTR are both expressed in the endosomes of PT cells. The loss of ClC-5 causes a major defect in receptor-mediated endocytosis and a consistent LMW proteinuria in Clcn5 KO mice and patients with Dent's disease, caused by inactivating mutations in CLCN5. Studies in the ClC-5 KO mice revealed that the defective endocytosis is due to a loss of the multi-ligand receptors megalin and cubilin at the brush border, reflecting a trafficking defect. Two cystic fibrosis (CF) mouse models were used to assess the role of CFTR in PT endocytosis. Cftr^-/-mice showed significant LMW proteinuria and impaired ¹²⁵ Ib2-microglobulin uptake, together with a decreased amount of cubilin, whereas the Cftr ^{[Delta]F/[Delta]F} mice were characterized by a large phenotypic heterogeneity. The endocytic defect in CF mice was moderate in comparison with ClC-5 KO mice, but it was confirmed in a cohort of CF patients. These results demonstrate that ClC-5 plays an essential role in apical endocytosis and PT cell trafficking, whereas CFTR inactivation leads to a moderate defect in PT endocytosis in mouse and man. The magnitude of the endocytosis defect caused by CFTR vs. ClC-5 loss likely reflects the distinct expression and distribution of these transporters along the PT.