Acute chest discomfort and dyspnea are 2 of the most common nontraumatic symptoms that prompt emergency department evaluations in the United States. The overlap between these presenting symptoms is considerable. In addition, each symptom calls for a broad differential diagnosis that requires rapid refinement according to details in the history, physical examination, blood biomarkers, and radiographic evaluation. This article highlights the epidemiology and the evidence supporting critical decision making, which makes judicious use of the clinical laboratory and diagnostic radiology in the evaluation of the acutely ill patient with chest discomfort and dyspnea.