NEPHROLITHIASIS shares with mineralization of bone a requirement for supersaturation and for modulation of crystal formation by cells and cell secretion products. The needs of the body demand a considerable traffic of calcium, phosphate, oxalate, and uric acid, which create multiple supersaturations in the renal tubule and the final urine. The additional need for water conservation exaggerates these supersaturations, especially in the distal nephron. As a result, late tubule fluid and urine are almost always supersaturated with at least calcium oxalate monohydrate. Defenses against nephrocalcinosis and stones include regulation of urine pH into an optimal zone, control of urine calcium and citrate concentrations, the addition to tubule fluid of at least six protein and glycosaminoglycan modulators of crystallization, and cellular responses to crystals, which include attachment and internalization. In principle, stones may arise from abnormalities at any of these points of compromise between homeostatic needs and the dangers of crystallization. At the present time, medical stone prevention concerns only what might be called physical chemistry, the interactions of ions and small molecules, whereas the most exciting research directions concern the cell and molecular biology of the defenses.