Barrett's esophagus is a premalignant condition, with dysplasia usually preceding the development of adenocarcinoma. Two main outstanding issues are firstly, the prediction of a subset of patients at higher risk of developing dysplasia and secondly, the treatment to try and avoid neoplastic progression. Whilst it is tempting to rely on the presence of low-grade dysplasia to predict subsequent malignant potential, low-grade dysplasia on its own is often an unreliable marker of such risk. As well as the difficulty in reproducing biopsies from the same site in the Barrett's segment, there is considerable interobserver variability and the histopathologist must be meticulous in excluding inflammatory changes secondary to severe gastro-esophageal reflux because these can mimic dysplasia. Low-grade dysplasia may also regress after adequate acid suppression.1 In Barrett's esophagus, the metaplastic cells have a higher proliferative rate. This activity is increased by acid exposure in vitro and in vivo via mitogen-activated protein kinase pathways which transmit growth regulatory signals to enhance cellular proliferation and decrease apoptosis.2 Mucosal acid exposure has been shown to promote epithelial proliferation,3,4 and increased epithelial proliferation in patients with Barrett's esophagus has been associated with a stepwise progression of dysplasia to adenocarcinoma.3,5,6 Conversely, acid suppression with proton-pump inhibitors (PPIs) has been shown to stabilize proliferative cell activity in Barrett's esophagus4,6,7 and may prevent dysplasia and reduce cancer risk.1,8 Also, cyclooxygenase-2 (COX-2) is over-expressed in the early transformation of esophageal epithelium in Barrett's esophagus and in the transition from low- to high-grade dysplasia and adenocarcinoma.9 There is speculation that chemoprevention could reduce the incidence of dysplasia and adenocarcinoma,8–10 and that trials of chemoprevention with antisecretory therapy combined with COX-2 inhibitors are therefore warranted.10 In this issue of the Journal, there are two papers about Barrett's esophagus. Kim et al. address the prevalence of Barrett's esophagus in an Asian country (Korea) and the associated demographics and risk factors (age, male sex, cigarette smoking, and acid regurgitation). Male sex has been identified previously as a major risk factor for the development of high-grade dysplasia and adenocarcinoma.11 The present study by Kim and colleagues also documents the predictive value of macroscopic markers, such as severe esophagitis, Barrett's ulcer, nodularity, and stricture formation. Interestingly, there were only two patients with severe esophagitis identified in the Korean study and only one patient with adenocarcinoma, but no dysplasia was seen. Whether this reflects the relatively small numbers in this series, the retrospective analysis or a different natural history remains to be elucidated. There is no doubt that smaller studies tend to overestimate the cancer risk.12,13 Larger patient series suggest that the risk of adenocarcinoma is more in the order of 1/176 patient-years.11 The second article by Amano et al. looks at factors affecting squamous epithelialization (and by inference, regression) of Barrett's esophagus. Intestinal mucin phenotype and maturation, COX-2 expression, and cellular proliferation were all identified as predominant predictors of poor squamous re-epithelialization. PPIs (albeit in low doses for short periods) were only effective in causing regression when the intestinal phenotype was not present. This may allow immuno-histochemical identification of a subgroup of patients with a higher malignant potential. But it may also mark a group that requires high-dose, long-term PPIs to heal reflux esophagitis and to maintain healing, and thereby decrease continued cellular proliferation. Whilst optimal medical management of Barrett's esophagus is uncertain,14 PPIs are an attractive class of medications; they have few side effects and are readily available. Accordingly, it may be appropriate to initiate long-term, high-dose PPIs as soon as the diagnosis is established, or even prior to endoscopy if the severity of reflux symptoms is such that the diagnosis is entertained.15 Although biomarkers would be a convenient method to target surveillance of high risk subgroups of Barrett's esophagus, chemoprevention with PPIs and/or COX-2 inhibitors may be a more cost-effective option for management of Barrett's esophagus in the long term. It must be emphasized, however, that PPIs need to be prescribed at standard or even high dose indefinitely in order for this strategy to be effective.