Gallstones are one of the most common digestive diseases with an estimated prevalence of 10%-15% in adults living in the western world, where cholesterol-enriched gallstones represent 75%-80% of all gallstones. In cholesterol gallstone disease, the gallbladder becomes the target organ of a complex metabolic disease. Indeed, a fine coordinated hepatobiliary and gastrointestinal function, including gallbladder motility in the fasting and postprandial state, is of crucial importance to prevent crystallization and precipitation of excess cholesterol in gallbladder bile. Also, gallbladder itself plays a physiopathological role in biliary lipid absorption. Here, we present a comprehensive view on the regulation of gallbladder motor function by focusing on recent discoveries in animal and human studies, and we discuss the role of the gallbladder in the pathogenesis of gallstone formation. 47:2112-2126 G allstones are one the most common gastrointestinal diseases that require hospitalization in the western world, 1 and this is a true health burden 2-4 with enormous costs estimated at 6.5 billion dollars each year in United States. 4,5 Because life expectancy and the incidence rate of obesity are both rising worldwide, 6 the incidence rate of gallstones may increase, often in the context of the "metabolic syndrome". 7 The estimated prevalence of gallstones is 10%-15% in the general population of developed countries. In the United States, approximately 20 million to 25 million adults have gallstones. The burden of the disease is highest (60%-70%) in American Indians followed by Hispanics of mixed Indian origin. In contrast, the rate is lowest (less than 5%) in Asian and African populations. 5 The prevalence is intermediate (10%-15%) in Caucasians in developed countries. In Europe, the Multicenter Italian Study on Cholelithiasis (MICOL) ultrasonographic survey, which was performed across Italy including 29,000 subjects aged 30-69 years, reported an overall prevalence rate of 18.8% and 9.5% in women and men, respectively. 8 Major risk factors for the development of gallstones have been better identified over the past years and include age, female sex, some genetic polymorphisms within a background of a complex genetic disorder, pregnancy, obesity and rapid weight loss on low caloric diets or fol-