Right upper quadrant (RUQ) pain is among the most common complaints in the emergency department. The differential diagnosis is broad and includes gastrointestinal (GI) and non-GI causes for pain. Evaluation of patients requires a combination of history, physical examination, laboratory testing, and diagnostic imaging. This article details the anatomy and physiology of the right upper abdomen and approach to the history and physical examination of the most common diseases encountered in the emergency department. “Can’t miss,” non-GI diagnoses are discussed. Best practices of laboratory and imaging, and treatment of most common diagnoses of RUQ pain are reviewed.