In patients with an acute chest pain syndrome the primary requirement is to diagnose or exclude acute myocardial ischemia or myocardial infarction. However, only 30% of patients admitted and evaluated for chest pain ultimately reveal the diagnosis of acute coronary syndrome.Traditionally, the initial evaluation of patients presenting with chest discomfort or pain to an emergency department or any general practice involves the triad of history, physical examination, and ECG and chest film evaluation. With the diagnostic routine of bedside enzymatic tests for cardiac biomarkers, it has become easier to identify acute coronary syndromes, but at the same time more compelling to pinpoint other differential diagnoses, once coronary syndromes are excluded. When a cardiac origin of any non-suggestive chest pain syndrome has been excluded, a broad spectrum of other causes for noncardiac chest pain needs to be evaluated. Potential underlying disorders are listed in this overview and grouped according to pathoanatomic origin into aortic, respiratory, and gastroesophageal disorders, musculoskeletal pathology, and somatization disorders. This article reviews both symptoms and diagnostic pathways in patients with noncardiac chest pain, and eventually offers a rational strategy for an efficacious workup of a wide spectrum of important differential diagnoses.