Chest pain (CP) is one of the most common symptoms of patients presenting to emergency departments (EDs) or emergency medical services (EMS). In the ED, approximately 50% of patients with CP suffer primarily from cardiac CP; for patients with CP who call the EMS first, that percentage is even higher (70%). Due to the serious consequences a primary false evaluation might have, such as acute coronary syndrome (ACS), a thorough initial workup is essential. The medical history, clinical inspection, electrocardiogram, and determination of biomarkers are cornerstones for establishing the correct diagnosis. Nevertheless, extracardiac causes of CP, including pulmonary embolism, aortic dissection, and gastrointestinal causes, should be considered from the very beginning. Risk scores such as the TIMI and GRACE scores for risk stratification in ACS and the Wells score for risk stratification in pulmonary embolism were shown to be valid in large clinical trials. Thus, they should be used more often in the ED.