The diagnosis of acute coronary syndrome (ACS) represents one of the most difficult tasks facing clinicians in the acute care environment. Accurately detecting ACS in patients presenting to the ED with chest discomfort or other high risk presentations for myocardial ischemia or infarction remains a complex diagnostic task. In addition, for emergency physicians, the evaluation of ACS is particularly stressful as the misdiagnosis of this disease process serves as a common source for medical malpractice litigation, resulting in approximately 20% of the dollars awarded annually. Currently, patients must be evaluated for myocardial necrosis, rest ischemia, and ultimately exercise-induced ischemia in the emergency setting to properly diagnose this condition in patients at risk for ACS. Myocardial biomarkers, serial 12-lead electrocardiograms, rest radionuclide imaging, graded exercise testing, and stress echocardiography and radionuclide imaging all represent usual approaches to a proper diagnosis in the ED. Ultimately, visualization of the coronary artery anatomy by cardiac catheterization remains the gold standard approach for diagnosis of atherosclerotic coronary artery disease, ruptured plaque and intra-luminal clot in patients with ACS.