Renal stone disease (nephrolithiasis) affects 5% of adults and is often associated with hypercalciuria. Hypercalciuric nephrolithiasis is a familial disorder in over 35% patients, and may occur as a monogenic disorder, or as a polygenic trait involving 3 to 5 susceptibility loci in man and rat, respectively. Studies of monogenic forms of hypercalciuric nephrolithiasis in man e.g. Bartter syndrome, Dent's disease, autosomal dominant hypocalcaemic hypercalciuria (ADHH), hypercalciuric nephrolithiasis with hypophosphataemia, and familial hypomagnesaemia with hypercalciuria have helped to identify a number of transporters, channels and receptors that are involved in regulating the renal tubular reabsorption of calcium. Thus, Bartter syndrome, an autosomal recessive disease, is caused by mutations of the bumetanide sensitive Na-K-Cl (NKCC2) co-transporter, the renal outer-medullary potassium channel (ROMK), the voltage-gated chloride channel, CLC-Kb, or in its beta subunit, Barttin. Dent's disease, an X-linked disorder characterised by low molecular weight proteinuria, hypercalciuria and nephrolithiasis, is due to mutations of the chloride/proton antiporter, CLC-5; ADHH is associated with activating mutations of the calcium-sensing receptor, which is a G-protein coupled receptor; hypophosphataemic hypercalciuric nephrolithiasis associated with rickets is due to mutations in the type 2c sodium-phosphate co-transporter (NPT2c); and familial hypomagnesaemia with hypercalciuria is due to mutations of paracellin-1 which is a member of the claudin family of membrane proteins that form the intercellular tight junction barrier in a variety of epithelia. These studies have provided valuable insights into the renal tubular pathways that regulate calcium reabsorption and predispose to kidney stones and bone disease.