Barrett's metaplasia-associated esophageal adenocarcinoma is one of the most rapidly increasing cancers in Western countries. Whereas early detection remains the cornerstone of prevention, chemoprevention is emerging as a complementary strategy. Carcinogenesis in Barrett's mucosa is a multistep process in which cellular growth becomes progressively dysregulated. Fortunately, the process of carcinogenesis is a protracted one, which provides ample opportunity for intervention. In this review, we will discuss various potential chemoprevention targets and rationale behind their use to prevent Barrett's related esophageal adenocarcinoma. We will also critically appraise the emerging preclinical and clinical literature regarding prevention of neoplasia in Barrett's esophagus.