Renal tubular fluid in the distal nephron is supersaturated with calcium and oxalate ions that nucleate to form crystals of calcium oxalate monohydrate (COM), the most common crystal in renal stones. It is not known how these nascent crystals are retained in the nephron to form calculi in certain individuals. Recent studies from this laboratory indicate that COM crystals can bind within seconds to anionic, sialic acid-containing glycoproteins on the apical surface of kidney epithelial cells in culture, suggesting one mechanisms whereby crystals could be retained in the tubule. Adherence of crystals to renal epithelial cells is inhibited by specific urinary anions such as glycosaminoglycans, uropontin, nephrocalcin, and citrate, each of which binds to the crystalline surface. Thus competition for the crystal surface between soluble anions in tubular fluid and anions on the apical cell surface could determine whether or not a crystal binds to the cell. Once bound, crystals are quickly internalized by renal cells in culture; reorganization of the cytoskeleton, alterations in gene expression, and initiation of proliferation can then ensue. Each of these cellular events appears to be regulated by a different set of extracellular factors. Identification of molecules in tubular fluid and on the cell surface that modulate crystal-cell interactions, as well as their mechanism of action, appears critical for understanding the pathogenesis of nephrolithiasis.