The number of gallstone patients is increasing in ageing populations with a high prevalence of metabolic syndrome and obesity. Recently variants of hepatic ATP binding cassette transporters have been identified as genetic susceptibility factors for gallstone disease, pointing to novel means for risk assessment and prevention. Although laparoscopic cholecystectomy is the mainstay of therapy for symptomatic gallbladder stones, the clinical management of gallstone disease is changing rapidly, with an increase in day case surgery and the advent of transluminal endoscopic surgery. Here, we summarize the molecular and genetic mechanisms of gallstone formation as well as the current evidence-based algorithms for diagnosis and therapy of gallbladder and bile duct stones.