Barrett's esophagus (BE), a premalignant lesion to esophageal adenocarcinoma is associated with long-standing, gastroesophageal reflux disease (GERD). BE is a multi-phase process: during the initiation phase, genetically predisposed individuals (mostly white men) suffering from clinical or occult reflux damage their distal esophagus and form a new cell phenotype (incomplete intestinal metaplasia). During the formation phase, this phenotype occupies an area of variable surface (short or long-segment BE). During the progression phase, the metaplastic epithelium either remains dormant or progresses to dysplasia and adenocarcinoma. We review the recent clinical and basic research literature that explores the interaction of the refluxate (acid, bile, etc.) with BE. Acid and bile reflux variably affect BE and may cause dysplasia or adenocarcinoma. Regardless of the underlying biology, a patient with BE may suffer from GERD symptoms or may remain asymptomatic. Acid may be synergistic to bile or it could be antagonistic and protective. Acid suppressive therapy, if profound and continuous enough to abolish symptoms and esophageal acid exposure, may decrease proliferation, increase differentiation and reduce BE surface. Overexpression of cyclooxygenase-2 (COX-2), not entirely independent of acid/bile reflux, may increase proliferation and increase the invasiveness and metastatic potential of Barrett's metaplasia and neoplasia. Clinically, both acid and bile reflux need to be inhibited, either with potent acid-suppressing drugs or anti-reflux surgery. Cyclooxygenase inhibition using aspirin, NSAIDs or the safer COX-2 inhibitors added to these anti-reflux therapies may enhance the therapeutic benefit. Many questions remain unanswered. We still do not know why only a fraction of patients with GERD develop BE, what factors of the refluxate (acid, bile, etc.) initiate metaplasia and/or promote carcinogenesis, which patients are at risk for malignancy, and what is the best chemopreventive strategy. Ablation therapies and endoscopic mucosal resection are still under study.