Renal stone disease may be seen as clinical symptom of an underlying pathological process predisposing to crystallization within the renal tract. Molecular genetics has allowed significant progress to be made in our understanding of renal tubular salt handling which underlies certain stone forming conditions. The molecular defect underlying these inherited tubular disorders often contributes to a significant metabolic risk factor for stone formation. In contrast, idiopathic renal stone formation relates to the interplay of environmental, dietary and genetic factors, with hypercalciuria being the most commonly found metabolic risk factor. The pathophysiological and genetic basis underlying familial hypercalciuria and calcium stone formation remains elusive. Here I will discuss known molecular players in the pathogenesis of hypercalciuria and the need for novel insights into why the majority of hypercalciuria remains unexplained