Gallstones form when the tenuous balance of solubility of biliary lipids tips in favor of precipitation of cholesterol, unconjugated bilirubin, or bacterial degradation products of biliary lipids. For cholesterol gallstones, metabolic alterations in hepatic cholesterol secretion combine with changes in gallbladder motility and intestinal bacterial degradation of bile salts to destabilize cholesterol carriers in bile and produce cholesterol crystals. For black pigment gallstones, changes in heme metabolism or bilirubin absorption lead to increased bilirubin concentrations and precipitation of calcium bilirubinate. In contrast, mechanical obstruction of the biliary tract is the major factor leading to bacterial degradation and precipitation of biliary lipids in brown pigment stones. Further understanding of the physical and metabolic factors of cholesterol and black pigment formation is likely to provide interventions to interrupt the earliest stages of gallstone formation.