The two membrane receptors megalin and cubilin are highly expressed in the endocytic pathway of the renal proximal tubule. Numerous ligands have been identified, and these receptors appear to be the main players responsible for the tubular clearance of proteins filtered in the glomeruli. Cubilin does not have an endocytosis signalling sequence and, since it binds to megalin, it appears that megalin in addition to internalizing its own ligands is also responsible for internalization of cubilin and its ligands. The importance of the receptors is underscored by the proteinuria observed in megalin-deficient mice and in dogs lacking functional cubilin.