Gastroesophageal reflux disease (GERD) is highly prevalent in the general population. Heartburn and acid regurgitation are considered the typical presentation of GERD, that however might represent a major pathogenic mechanism in patients with chest pain without coronary artery disease. Chest pain in this instance is often successfully treated with high-dose antisecretory drugs, but the pathogenetic mechanism remains unclear. Further research is needed to clarify the role of GERD on the pathogenesis of chest pain and to ascertain whether a medical or surgical anti-secretory treatment could represent a possible approach. Patients with non-cardiac chest pain of unknown origin should be carefully screened for the occurrence of GERD.