Oesophageal adenocarcinoma is one of the most deadly human malignancies. Gastro-oesophageal reflux disease (GERD) has been established as a strong risk factor for oesophageal adenocarcinoma, and more than 40% of adult Americans experience regular GERD symptoms. GERD can be complicated by oesophagitis, and by replacement of oesophageal squamous mucosa with metaplastic, intestinal-type epithelium (Barrett's oesophagus) that is predisposed to malignancy. Cancers in Barrett's oesophagus arise through a sequence of genetic alterations which endow unlimited proliferative capacity upon the cells by affecting components of the cell cycle clock apparatus-the pivotal molecular machinery in the cell nucleus that controls whether a cell will proliferate, differentiate, become quiescent or die. This report describes how the genetic abnormalities that have been recognized in Barrett's oesophagus might promote carcinogenesis through effects on the cell cycle clock machinery. The goal of this review is to provide the clinician with a useful conceptual basis for evaluating studies on the molecular mechanisms underlying the progression from metaplasia to carcinoma in Barrett's oesophagus.