It is proposed that gallstones stem from insufficiency of micronutrient antioxidants relative to the load of oxidants and/or oxidation-prone substrates within hepatocytes in such a way that ancillary hepatobiliary resources, including bilirubin with lactoferrin and mucin, are mobilized to combat oxidative stress but inadvertently promote lithogenesis. Aberrant activities of hepatic cytochrome P450 mono-oxygenases and of haem oxygenase are integral to this template, because differential inhibition or activation of these enzymes would help to rationalize the spectrum of human gallstone composition and also the different outcomes when animals are fed the same lithogenic diets. The hypothesis is based on a decade of work on another lithogenic disease, chronic pancreatitis. It accommodates observations on human and experimental gallstones, it is testable and, as shown by studies of chronic pancreatitis, has implications for primary disease prevention.