Gallstone disease is prevalent in western society, with 10–15 % of adults having gallstones (Stinton and Shaffer, Gut Liver 6(2):172–87, 2012). In the USA, 500,000–750,000 cholecystectomies are performed annually. Given the prevalence of biliary disease, it is important to understand the spectrum of gallstone-related pathologies and how to treat them. The major problems caused by gallstones are symptomatic cholelithiasis; acute cholecystitis; choledocholithiasis; cholangitis; and biliary pancreatitis. In addition, the surgeon may encounter a patient with acute acalculous cholecystitis or gallstone ileus. This chapter offers an overview of each of these clinical entities and outlines a diagnostic and treatment strategy for each.