The incidence of the adenocarcinoma of the esophagus (ACE) has dramatically for the last decades in western countries, which has been associated with a parallel increase in the incidence and prevalence of symptoms associated with gastroesophageal reflux diseases (GERD) and Barrett's esophagus (BE). Both conditions are now considered risk factors for ACE. Different pathways, including overexpression of cyclooxygenase (COX) isoenzymes, has been proposed to explain the carcinogenic process leading from normal esophagus to esophagitis, BE and ACE. The survival rate in patients with ACE is very low because of the poor outcomes of surgery and the limited benefits obtained with concomitant chemo-radiotherapy Several strategies based on early detection and surveillance of preneoplastic lessions have failed to have a global and significant impact on the prognosis of the ACE. Recent epidemiological and experimental studies suggest that chemoprevention could be useful in the management of patients with GERD and especially in those with BE. The current therapy with protom pump inhibitors (PPI) is effective to reduce the esophageal acid exposure, to improve reflux symptoms, and to heal inflammatory injuries, but probably is not enough to avoid the dysplastic progression of the metaplastic epithelium. Regular use of COX inhibitors (aspirin and other non steroid antiinflamatory drugs) has been associated with reduction of the risk of ACE and to decrease the incidence of ACE in animal models. In humans, the association of PPI with COX inhibitors could be a cost-effectiveness strategy but direct evidence is lacking. Other potential agents that have shown some chemoprevention potential include troglitazone, free radical scavengers, tamoxifen or prostaglandin receptor blockers, but the available scientific evidence is still poor and not ready to be tested in humans.