Esophageal adenocarcinoma has undergone a marked increase in incidence in Western cultures. The cause of this rise is unclear, and multiple putative causal factors have been implicated in the literature. Although data regarding some of these factors are suggestive, none appear to completely explain the observed trends. Given the complexity of cancer biology, the variety of causative and protective factors involved, and the difficulty in accurate measurement of exposures and outcomes, isolating one or few causative factors is challenging. Understanding the driving force(s) behind these trends may require a better understanding of the interaction between risk factors, as well as the multiple ways in which a single risk factor may affect the pathogenesis of the tumor.