Mutations in the sodium phosphate co-transporters NPT2a [1–3] and NPT2c [4, 5] have been associated with intraluminal stones (nephrolithiasis) and mineral deposits in the renal parenchyma (nephrocalcinosis) in patients with familial forms of hypophosphatemia. In genome-wide association studies, NPT2a has also been associated with nephrolithiasis  and altered renal function [7, 8]. With both genetic abnormalities affected individuals show renal phosphate-wasting, high circulating levels of 1,25(OH)2D, and absorptive hypercalciuria as a result of increased intestinal uptake of calcium [4, 5, 9, 10], and oral phosphate supplements are currently thought to reduce the risk for renal mineralization by lowering circulating levels of 1,25(OH)2D and absorptive hypercalciuria . However, the relative contribution of genotype, dietary calcium and phosphate, and modifiers of mineralization to the formation of renal mineral deposits is unclear. Our recent work suggests that reduced levels of osteopontin (Opn), an extracellular matrix factor affecting binding of phosphate to hydroxyapatite crystals, contribute to the development of nephrocalcinosis in Npt2a-/- mice . This may be due to the fact that Npt2a-/- mice respond differently to dietary phosphate when compared to WT mice . Further evaluation in the Npt2a-/- cohort on different diets suggests that urinary calcium excretion, plasma phosphate, and FGF23 levels appear to be positively correlated to renal mineral deposit formation, while urine phosphate levels and the urine anion gap, an indirect measure of ammonia excretion, appear to be inversely correlated . In addition, local tissue levels of Pi generated by tissue nonspecific alkaline phosphatase (Tnsalp) and ectonucleoside triphosphate diphosphohydrolase 5 (Entpd5) may be important as suggested by decreased skeletal mineralization in the absence of these enzymes [14, 15].