Recent investigations into Barrett's oesophagus at the level of individual crypts have found significant genetic heterogeneity within a single lesion. Furthermore, this genetic diversity has been shown to predict cancer development. In the present article, we review the genetic alterations implicated in disease progression in Barrett's oesophagus and discuss how genetic diversity could arise during tumorigenesis. Three arguments are discussed: a high mutation rate coupled with strong selection, clonal interaction driving progression, and a hitherto unidentified alteration that disrupts epithelial cell homoeostasis. Suggestions are made for future research to distinguish which of these theories is the predominant mechanism in Barrett's oesophagus-associated tumorigenesis.