Most epithelial cancers occur on the background of chronic exposure to damaging agents which is reflected in the long lag phase from development of a pre-invasive lesion to the development of a carcinoma. Luminal refluxate has long been recognized to be associated with Barrett's oesophagus, although causal mechanisms have not been clearly defined. Recently, obesity and dietary nitric oxide have also been implicated in the disease pathogenesis. We have demonstrated that acid can alter cell kinetics and, together with nitric oxide, can induce double-stranded DNA breaks. Aside from exposure to luminal factors, the stromal micro-environment may also be important. There is increasing evidence to suggest that inflammatory pathways such as TGF (transforming growth factor) beta may play a role in Barrett's oesophagus carcinogenesis. Hence stromal-epithelial-luminal interactions may influence cell behaviour. As sequelae to this, it is possible that the niches created by the micro-environment may influence genetic epithelial diversity observed within the Barrett's oesophagus segment.