Esophageal adenocarcinoma (EAC) is a highly lethal tumor and is currently the most rapidly rising incidence cancer in the Western world. Numerous risk factors in the development of Barrett's esophagus (BE) (a precursor of EAC) and EAC itself have been identified and are likely multifactorial. Gastroesophageal reflux disease (GERD) is a significant risk factor for BE and EAC; however, only a minority of patients with chronic GERD actually develop BE. Thus, other risk factors that modulate reflux-related inflammatory and neoplastic effects on esophageal epithelium must exist. Epidemiologic data have prompted initiation of chemopreventive trials using aspirin and proton pump inhibitors in the treatment of BE and EAC. Further research should also clarify the role of risk factors such as ethnicity and obesity in BE and EAC development and progression. Identification of prognostic factors would allow better risk stratification of patients and ultimately impact the rising incidence of EAC.