Barrett's esophagus (BE) is a condition affecting an estimated 2 million persons in the United States in which the squamous epithelium has been replaced by a metaplastic columnar epithelium as a complication of chronic gastro esophageal reflux disease. Persons with BE are at a much higher risk of developing esophageal adenocarcinoma. Additional markers of cancer risk are needed to identify the patient subset at greatest cancer risk, as intensive endoscopic surveillance of all patients with BE is not cost effective, and existing medical therapies have not been proven to prevent cancer. Loss of the normal mechanisms that insure genomic stability may be an early event in BE neoplastic progression and telomere shortening has become of increasing interest as a source of chromosomal instability. The damaged Barrett's epithelium is chronically regenerating, and due to the "end replication problem", in the absence of telomerase, telomeres shorten in length at each cell division. In order to directly test telomere length in BE, a quantitative histologic assay of telomere length is used which employs in situ hybridization with a telomere specific probe. In each biopsy, the fluorescence intensity of the telomeres of epithelial cells was compared to the telomeres of stromal cells. Whereas gastric mucosal biopsies show mean epithelial: stromal telomere ratios of 0.9, in BE the mean epithelial: stromal telomere ratios are only 0.6. Some of these patients with telomere shortening had benign metaplasia without loss of tumor suppressors, raising the possibility that shortening of telomeres is a very early event in Barrett's esophagus neoplastic progression. These initial observations suggest that telomere shortening may be an intermediate biomarker of early events in neoplastic progression in BE. Further examination of chromosomal instability on the same patient tissue sections using fluorescent in situ hybridization will begin to elucidate telomere shortening as consequential or causative in the process of cancer development.