Tamm-Horsfall (TH) protein is the most abundant protein in human urine. It plays dual roles in the formation of calcium oxalate stones depending on its structure, concentration and urine properties. In this paper, the chemical basis of the effects of TH protein on the formation of calcium oxalate stones was systematically discussed in view of the concentration of TH protein, the urinary pH, ionic strength, metallic ions, the cooperative effect of citrate and TH protein, and the effect on the adhesion of calcium oxalate crystals to the renal cell membrane. The differentiation between TH protein and its analog was also comparatively discussed.