Epigastric pain is an extremely common complaint in the emergency department and has an associated broad differential diagnosis. In the differential it is important to consider cardiac causes that may be mistaken for gastrointestinal disorders as well as various serious intra-abdominal causes. This article highlights the limitations in laboratory testing and guides providers through the appropriate considerations for advanced imaging. Special attention is focused on acute pancreatitis, esophageal emergencies, and peptic ulcer disease/gastritis and their associated complications.