Barrett's esophagus (BE) is established as the primary precursor lesion of esophageal adenocarcinoma (EAC). The risk of esophageal cancer is 30-125 times greater compared to an age-matched population and survival rates are low, with only 15% of patients being alive 5 years after initial diagnosis. Therefore, surveillance strategies in BE are recommended to detect intraepithelial neoplasia and early carcinoma which in turn can be resected using endoscopic methods. Nevertheless, surveillance strategies have not had a major benefit in decreasing the incidence of EAC. Thus, attention should also be given to potential targets for prevention strategies that might arrest or delay the progression of BE to EAC. This article focuses on known and postulated targets for prevention of distal esophageal cancer.