Abstract: Barrett esophagus is the known precursor lesion of esophageal adenocarcinoma; however, the natural history of Barrett esophagus and its associated dysplasia is a matter of considerable debate and difficult to establish on a patient-by-patient basis. Clinical management and surveillance are currently limited by a lack of efficient and accurate predictive biomarkers of progression, and the incidence of esophageal adenocarcinoma has increased at an alarming rate. This phenomenon has attracted considerable interest in the molecular pathogenesis of Barrett esophagus and esophageal adenocarcinoma. Neoplastic transformation of Barrett esophagus appears to be a complex disease process in which multiple defective clones accumulate mutations producing a lesion with significant heterogeneity and clonal diversity. P16 inactivation, p53 loss of heterozygosity, and DNA ploidy abnormalities are all significant events in the progression of Barrett esophagus. It is clear that many molecular alterations take place during the neoplastic transformation of Barrett esophagus, and our improved understanding of the molecular pathogenesis has contributed to the progress of predictive biomarker development in preclinical studies. Although many genetic and epigenetic abnormalities have been identified, no molecular tests are available in routine clinical practice. Ideally, a panel of predictive biomarkers would allow for risk stratification into low- and high-risk subgroups, which could help decide which patients receive appropriate follow-up or therapeutic intervention. This review discusses current issues with the diagnosis and surveillance of Barrett esophagus and highlights the most promising predictive biomarkers that may supplement histology for optimal patient management.