Chest pain is common and the initial clinical presentation is often nonspecific. The emergency physician faces the challenge of correctly identifying those patients with a life-threatening cause of chest pain while avoiding unnecessary hospital admissions. Three important life-threatening causes of chest pain are aortic dissection, pulmonary embolism, and acute coronary syndrome. Simple clinical tools should be applied to exclude these diagnoses and avoid CT whenever possible. A normal serum d-dimer measurement can safely exclude pulmonary embolism and aortic dissection, although elevated d-dimer levels are common and nonspecific. Promising markers for early myocardial ischemia have been described and should be developed further. CT provides a first-line imaging tool for aortic dissection and pulmonary embolism based on its wide availability, speed, and high level of diagnostic performance. Improvements in CT scanner technology now enable in-depth data on the coronary arteries. Although angiographic information is limited in its relation to physiologic lesion significance, coronary CT is used to safely diagnose or exclude coronary disease as a source of chest pain in emergency department patients. "Triple rule-out" protocols designed to simultaneously assess the aorta, pulmonary arteries, and coronary arteries are a compromise between dedicated protocols for each diagnosis. The diagnostic value and appropriate clinical use of these protocols remain to be shown by randomized, controlled, outcomes-based trials.