Chronic gastro-oesophageal reflux disease can induce a metaplastic change of the distal oesophagus called Barrett's oesophagus whereby the normal squamous epithelium is substituted by a columnar epithelium. Patients with Barrett's oesophagus are at increased risk of oesophageal adenocarcinoma which occurs through dysplastic stages with increasing degree of cellular and architectural disorganization. Barrett's oesophagus represents an ideal model to study the genetic events supporting the onset of an invasive tumour since patients with this condition are surveilled with endoscopic tissue sampling until high grade dysplasia or intramucosal carcinoma develop. However, due to the relatively low incidence of this disease compared to other cancers, i.e. colon and breast, it is only recently that researchers have concentrated on understanding the genetic events supporting the onset of Barrett's and its transformation to cancer. Here, we review the knowledge acquired so far on the genetic and molecular alterations along the oesophageal metaplasia-dysplasia-carcinoma sequence.