Calcium stones occur because renal tubular fluid and urine are supersaturated with respect to calcium oxalate and phosphate. The process of stone formation includes crystal nucleation, growth, aggregation, and attachment to renal epithelia. Urine contains macromolecules that modify these processes and may protect against stone formation. Attention has focused especially on inhibitors of crystal growth, and several have been isolated from urine, including nephrocalcin, an acidic phosphorylated glycoprotein that contains several residues of gamma-carboxyglutamic acid per molecule; osteopontin (uropontin), a phosphorylated glycoprotein also found in bone matrix; uronic acid-rich protein, which contains a covalently bound glycosaminoglycan residue; and several others. Abnormalities in structure and/or function have been detected in some of these proteins in stone formers' urine. However, the overall ability of urinary macromolecules to inhibit calcium oxalate crystal growth is often normal in stone formers. Recently, attention has been focused on the ability of these molecules to inhibit other stages in stone formation. Nephrocalcin can inhibit crystal nucleation, for example, and both nephrocalcin and Tamm-Horsfall protein inhibit crystal aggregation. Nephrocalcin and Tamm-Horsfall protein from stone formers are less active in preventing aggregation, and under some conditions, Tamm-Horsfall protein may promote the formation of crystal aggregates, especially in the presence of high concentrations of calcium. The structural abnormalities responsible for impaired inhibitory activity are not completely understood.