Chest pain is the presenting complaint in over 6 million emergency department visits each year. Differentiating acute coronary syndrome (ACS) from other, noncardiac causes of chest pain is imperative in emergency practice. This article reviews the current medical evidence and published guidelines for the diagnosis of undifferentiated chest pain. A MEDLINE database search was conducted for relevant English language articles discussing an approach to undifferentiated chest pain. The published guidelines of the American College of Emergency Physicians, the American Heart Association, and the American College of Cardiology were also reviewed. The data surveyed suggest that, for all adult patients complaining of nontraumatic chest pain, a cardiac etiology for their presentation should be considered. History, physical examination, electrocardiogram, chest radiography, and to a lesser extent laboratory results can help differentiate ACS from other emergent diagnoses, e.g., aortic dissection, esophageal rupture, pulmonary embolus, pneumothorax, pneumonia, and pericarditis. No single feature of a patient's history, physical examination, or diagnostic test results can diagnose ACS to the exclusion of other causes of chest pain. Consequently, patients presenting with a complaint of chest pain frequently require serial evaluations, and admission to an observation unit or the hospital.