The causal relationship between GERD and esophageal adenocarcinoma, although unclear just a few decades ago, now is established fairly well. The physiologic changes and the biocellular alterations of the damaged esophageal mucosa are documented better. Despite this knowledge, the dramatic increase in the incidence of esophageal cancer cannot be explained. The absolute risk of esophageal adenocarcinoma arising from GERD is low, and, at present, does not justify population-screening programs. Still, with the notion that adenocarcinoma of the esophagus is an aggressive cancer once documented, important questions still are in need of answers for patients suffering from reflux symptoms. Patients who have reflux disease are not necessarily symptomatic. It remains unclear if patients experiencing reflux symptoms should undergo mandatory endoscopy with biopsies at the esophagogastric junction. Furthermore, metaplasia of the lower esophagus often is not readily recognizable at endoscopy, and only biopsies can document abnormal histology. A severe and prolonged history of reflux always should orient to the possibility of a reflux-related columnar-lined esophagus. Once documented, Barrett's esophagus needs to be seen as a premalignant condition not necessarily leading to adenocarcinoma formation; despite their increased risk of tumor formation, most patients who have Barrett's esophagus die of other causes. During regular endoscopic follow-up, multilevel circumferential biopsies should document the evolution of the histologic changes in the lower esophagus and at the gastroesophageal junction of these patients. It is the only method available to document the appearance of dysplasia. It still is unclear if medicine or surgery provides the best quality of life and the best protection against the development of dysplasia and the possible progression toward adenocarcinoma formation when intestinal metaplasia is present in the esophagus.