We have recently gained unprecedented insight into genetic factors that determine risk for Barrett’s esophagus (BE) and progression to esophageal adenocarcinoma (EA). Next-generation sequencing technologies have allowed us to identify somatic mutations that initiate BE and track genetic changes during development of tumors and invasive cancer. These technologies led to identification of mechanisms of tumorigenesis that challenge the current multi-step model of progression to EA. Newer, cost-effective technologies create opportunities to rapidly translate the analysis of DNA into tools that can identify patients with BE at high risk for cancer, detect dysplastic lesions at earlier stages, and uncover mechanisms of carcinogenesis.