The definition of Barrett's esophagus (BE) varies worldwide, particularly with regard to the need to identify goblet cells in esophageal biopsies in order to diagnose this condition. Problems related to the need to identify goblet cells to diagnose BE include the facts that goblet cells are uncommon in pediatric patients with BE, a small percentage of adults with columnar metaplasia of the esophagus do not contain goblet cells, the chances of detecting goblet cells are proportional to the length of columnar metaplasia, sampling error is common, and interpretation and differentiation of goblet cells vs. pseudogoblet cells may be difficult in some circumstances. In addition, goblet cells have been shown to wax and wane over the natural history of BE. Recent studies suggest that the background nongoblet epithelium in BE is biologically intestinalized, and shows a variety of molecular abnormalities similar to the goblet cell-containing epithelium. In addition, several retrospective and outcome studies suggest a well-defined risk of neoplasia in patients with esophageal columnar metaplasia, but without goblet cells. There are important clinical and economic implications to these findings and also with regard to the definition of BE. This review provides evidence to suggest that a diagnosis of BE should not require demonstration of goblet cells in mucosal biopsies, and offers considerable data to support the notion that a nongoblet epithelium is also at risk of malignancy. Guidelines for the diagnosis of BE need to consider revisions that take into account new data regarding nongoblet cell epithelium in BE, and the difficulties in recognizing columnar metaplasia that measures less than 1 cm in length.