In the United States, 10% to 15% of adults are affected by gallstones, and cholesterol gallstones are the most prevalent subtype. Risk factors for developing gallstone disease include female sex; older age; certain medications; and having type 2 diabetes mellitus, nonalcoholic fatty liver disease, obesity, rapid weight loss, or hemolytic anemia. Nearly 80% of gallstones are found incidentally and remain asymptomatic. When symptomatic, gallstone disease usually presents as sudden onset right upper quadrant or epigastric abdominal pain. Common complications of gallstones include cholecystitis, choledocholithiasis, gallstone pancreatitis, and ascending cholangitis. The Murphy sign is a specific physical examination finding for acute cholecystitis. Ultrasonography is the initial imaging choice for detecting gallstones and acute cholecystitis. A hepatobiliary iminodiacetic acid (HIDA) scan can be used to evaluate for cholecystitis in patients with negative or equivocal ultrasound findings. Magnetic resonance cholangiopancreatography (MRCP) is an accurate, noninvasive diagnostic test to identify choledocholithiasis, certain malignancies, and biliary obstruction. Nonsteroidal anti-inflammatory drugs are safe and effective in treating pain from acute cholecystitis and biliary colic. Laparoscopic cholecystectomy is the treatment of choice for most patients with biliary colic or acute cholecystitis. Ursodeoxycholic acid and chenodeoxycholic acid should not routinely be used to treat gallstone disease, but they can be used as a nonsurgical alternative for certain patients. Postcholecystectomy syndrome is a potential postoperative complication that presents with abdominal pain, bloating, and diarrhea. (Am Fam Physician. 2024;109(6):518-524. Copyright © 2024 American Academy of Family Physicians.)