Chest pain is the most common cause of medical referral. Is one of the cardiac problems symptoms but it can be associated with other organs damage or failure. The prompt and accurate initial diagnosis is crucial to select high-risk patients and to commence appropriate management. The ability to distinguish the chest pain provoked by important cardiac disease from similar symptoms triggered by other organs disorders depends on clinical experience of the doctor and also on the skill to perform differential diagnosis. In the diagnostic workup it is necessary to take into account the chest pain characteristics, duration of chest pain, triggering and relieving factors. The symptoms and signs that may accompany the chest pain are of utmost importance as well as the results of accurate and specific diagnostic examinations. The life-threatening diseases are: unstable angina and myocardial infarction, aortic dissection, pulmonary embolism. After the above are excluded one should consider other causes such as pulmonary, gastrointestinal and musculoskeletal diseases. This paper outlines the sequential differential diagnosis of the most common causes of chest pain with the special emphasis of life-threatening disorders. Each described disease is thoroughly discussed including the chest pain characteristics, the most common accompanying signs and symptoms and the results of important and necessary examination, that allow to establish the correct diagnosis and to start the appropriate management.