Barrett's metaplasia is found in approximately 12% to 18% of patients undergoing upper endoscopy for symptoms of reflux. Barrett's metaplasia is a premalignant condition and remains the number one risk factor for developing esophageal adenocarcinoma. There has been an increase in the incidence of esophageal adenocarcinoma in the past two decades, making it the most rapidly rising cancer in the United States and Western Europe. This article describes the progression from Barrett's metaplasia to esophageal adenocarcinoma and predictors for the development of adenocarcinoma in Barrett's metaplasia. Barrett's metaplasia represents a histological mosaic, with dysplastic tissue adjacent to non-dysplastic tissue. The histologic changes leading to adenocarcinoma are accompanied by alterations at the molecular level, including the accumulation of gene mutations and changes in gene expression. The determination of the molecular events that occur in the transition from normal esophageal squamous mucosa to dysplasia and to esophageal adenocarcinoma have lead to a better understanding of the process of the transformation to adenocarcinoma. This knowledge will lead to better biomarkers to diagnose and assess cancer risk.