Carcinogenesis in Barrett's esophagus involves the accumulation of DNA abnormalities that enable cells to 1) provide their own growth signals; 2) ignore growth-inhibitory signals; 3) avoid apoptosis; 4) replicate without limit; 5) sustain angiogenesis; and 6) invade and proliferate in unnatural locations. This report reviews recent publications describing molecular abnormalities in Barrett's esophagus that could lead to the acquisition of these key physiologic hallmarks of malignancy. Some recent reports suggest that the gastroesophageal reflux of acid and bile can activate molecular pathways that promote proliferation and interfere with apoptosis in Barrett's metaplastic cells. Inactivation of the p16 and p53 tumor suppressor genes through promoter methylation, gene mutation, or loss of heterozygosity appears to be important for carcinogenesis in Barrett's esophagus. Finally, this report discusses recent data regarding the role of the Cdx2 gene in the development of esophageal intestinal metaplasia.