Kidney stone disease (KSD) is heritable, affects ~10% of adults, and associated with abnormalities of mineral metabolism. KSD pathophysiology is poorly defined and therapeutic strategies are limited. We used Mendelian randomisation and colocalisation to identify three genetic variants increasing KSD risk via increased serum calcium or decreased serum phosphate concentrations (odds ratios for genomic regions=4.30, 11.42, and 13.83 per 1 standard deviation alteration) that account for 11-19% of KSD cases due to reduced calcium-sensing receptor (CaSR)-signal transduction, increased urinary phosphate excretion, and impaired 1,25-dihydroxyvitamin D inactivation via diacylglycerol kinase delta (DGKD, rs838717), solute carrier family 34 member 1 (SLC34A1, rs10051765), and cytochrome P450 family 24 subfamily A member 1 (CYP24A1, rs6127099), respectively. In silico analyses revealed that targeting CASR, DGKD, or CYP24A1 to decrease serum calcium, or SLC34A1 to increase serum phosphate may reduce KSD risk, and in vitro studies demonstrated that positive CaSR-allosteric modulation ameliorates CaSR-signal transduction impaired by reduced DGKδ expression or KSD-associated DGKD missense variants. These studies suggest that DGKD-, SLC34A1-, and CYP24A1-associated variants linked to reduced CaSR-signal transduction, increased urinary phosphate excretion, and impaired 1,25-dihydroxyvitamin D inactivation, respectively, commonly cause KSD. Genotyping patients with KSD may facilitate personalized risk stratification and targeted pharmacomodulation to prevent KSD.