In the recent 5 years, several important conceptual changes in the understanding of cholesterol gallstone formation have occurred. This article discusses the molecular basis of the disease, as we understand it today. The discovery of a vesicular carrier of biliary lipids and the metabolic regulation of biliary cholesterol secretion have markedly modified our understanding of the pathogenesis of cholelithiasis, giving more emphasis to molecular and cell biology aspects, rather than to physicochemistry, as occurred in the late seventies (micellar theory). The critical step in gallstone formation is cholesterol crystallization and it occurs after vesicle aggregation and fusion. This process is probably dependent of hepatic glycoproteins secreted into bile, presumably associated to the vesicular carrier of biliary cholesterol. Risk factors such as sex, obesity, sexual hormones, and diet seem to modify either biliary cholesterol secretion, and/or nucleation (crystallization) in the gallbladder, and/or gallbladder motility. It seems most likely that gallstones is a multifactorial disease, dependent of an interactions between environmental and genetic, or ethnic, factors.