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Gallstone-related disease is among the most common clinical problems encountered worldwide. The manifestations of cholelithiasis vary greatly, ranging from mild biliary colic to life-threatening gallstone pancreatitis and cholangitis. The vast majority of gallstone-related diseases encountered in an acute setting can be categorized as biliary colic, cholecystitis, choledocholithiasis, and pancreatitis, although these diagnoses can overlap. The management of these diseases is uniquely multidisciplinary, involving many specialties and treatment options. Thus, care may be compromised due to redundant tests, treatment delays, or inconsistent management. This review outlines the evidence for initial evaluation, diagnostic workup, and treatment for the most common gallstone-related emergencies. Key principles include initial risk stratification of patients to aid in triage and timing of interventions, early initiation of appropriate antibiotics for patients with evidence of cholecystitis or cholangitis, patient selection for endoscopic biliary decompression, and growing evidence in favor of early laparoscopic cholecystectomy for clinically stable patients.