Renal stones form in the late collecting duct in a complex milieu involving salts and protein components of the urine together with direct interactions at the epithelial cells lining the duct. The operation of newly discovered physiological controls that limit crystal formation by feedback mechanisms which sense the luminal environment are discussed. Adhesion at the epithelial surface and intracellular processing of crystals comprise a previously unrecognised mechanism for limiting crystal growth, which may be disrupted resulting in disease. Dent’s disease is discussed as a paradigm of a complex renal tubular disease resulting in renal stone formation. Defects in endosomal acidification, due to ablation of the CLC-5 voltage-gated Cl<sup>–</sup> channel, result in defects in both proximal and collecting duct endosomal traffic leading to stone formation.