The incidence of esophageal adenocarcinoma (EAC) is rapidly rising in the Western world, and accounts for 2% of all cancer-related deaths. The precursor lesion for EAC is Barrett’s esophagus (BE), which is strongly associated with gastro esophageal reflux disease. A major limitation to the study of EAC has been the absence of tractable and genetically modifiable preclinical models of BE. A mouse model of BE and EAC that resembles human disease could provide novel insights in the origins and molecular pathogenesis of BE. In addition, validated animal models could help stratify BE patients, given the limited predictive power of current standard endoscopic measures and clinical assessment. We recently generated such a novel transgenic mouse model for BE and EAC that has provided fundamental insights into the early pathogenesis of BE, and offers a molecular basis for an emerging paradigm shift regarding the cell of origin of BE and EAC. Our data suggest potential origins of BE from the gastric cardia, a role of bile acid and hypergatrinaemia for carcinogenesis, a growing importance for columnar-like epithelium, and a critical role for Notch signaling.