The goals of treatment of Barrett's esophagus (BE) include relieving reflux symptoms, healing inflammatory lesions, and preventing esophageal adenocarcinoma. Reduction of acid reflux is believed to prevent progression of BE. A critical question is whether or not regression of BE occurs in response to therapy with proton pump inhibitors. The natural history of BE is altered both by the use of medications (over-the-counter or prescribed) and by endoscopic surveillance with periodic biopsies. Regression occurs when the length and surface area of BE decreases, along with the emergence of islands of squamous epithelium in the BE segment. However, the extent of regression is difficult to assess because intestinal metaplasia may underlie the islands of squamous epithelial regrowth. Sampling by endoscopic biopsy is useful in ruling out progression of BE to dysplasia or adenocarcinoma; however, complete regression of the lesion cannot be definitively proven by this technique. To date, published clinical trials of proton pump inhibitor therapy in patients with BE provide evidence of increases in squamous islands in the BE segment, but do not provide convincing data in support of complete regression of BE. In a review of prospective studies of the treatment of BE with proton pump inhibitors (PPIs) (with or without surgery), only 3 of 123 patients had apparent complete reversal of BE. This article reviews the current understanding of regression in BE following treatment with PPIs.