The paracellular reabsorption of Ca2+ and Mg2+ in renal tubules plays an important role for the regulation and homeostasis of these cations. The genetic analysis of rare human disease phenotypes significantly contributed to our current understanding of the physiology of paracellular transport. In this context, the identification of mutations in CLDN16 as the underlying cause of a rare Ca2+ and Mg2+ -wasting tubular disorder was of special importance for further research activities (Simon et al, 1999). CLDN16 encodes a tight junction protein of the claudin family. Claudins have been shown to be the key components of the tight junction protein complexes which allow the formation of ion selective paracellular pathways varying from one tissue to the other. As an example, it has been demonstrated that claudin-16 and claudin-19 require each other for assembly into tight junctions in the thick ascending limb and are both parts of a cation selective paracellular “channel”. In a recent genome-wide association study, polymorphisms in CLDN14 were associated with nephrolithiasis. The exact mechanism which is responsible for this association is not known, but there might be a direct role of claudin-14 for renal Ca2+ reabsorption since CLDN11/14 double knockout mice have slightly increased urinary excretion rates for Ca2+ but also for Mg2+. Alternatively, CLDN14 could be involved in acid-base homeostasis because it has been reported to act as a negative regulator of protons, bicarbonate and ammonium ions in the distal nephron.