Calcium nephrolithiasis is a common condition. Family-based genetic linkage studies and genome-wide association studies (GWASs) have uncovered a run of important candidate genes involved in renal Ca(++) disorders and kidney stone diseases. The susceptible genes include NKCC2, ROMK and ClCkb/Barttin that underlie renal salt excretion; claudin-14, -16 and -19 that underlie renal Ca(++) excretion; and CaSR that provides a sensing mechanism for the kidney to regulate salt, water and Ca(++) homeostasis. Biological and physiological analyses have revealed the cellular mechanism for transepithelial Ca(++) transport in the kidney that depends on the concerted action of these gene products. Although the individual pathogenic weight of the susceptible genes in nephrolithiasis remains unclear, perturbation of their expression or function compromises the different steps within the integrated pathway for Ca(++) reabsorption, providing a physiological basis for diagnosing and managing kidney stone diseases.