Chest pain is a common clinical problem that can be caused by a broad spectrum of diseases other than coronary artery disease or acid re fl ux. The diagnosis of non cardiac, non esophageal chest pain can be challenging. The chronic occurrence of chest pain interferes with the daily life routine, mood and productivity of those affected by this condition and therefore implies an enormous socio-economic burden in the community. This chapter offers an overview of some of the most relevant conditions that need to be considered in the differential diagnosis of a patient presenting with chest pain, once that a cardiac and/or an esophageal origin of the symptom has been properly excluded.