Oesophageal cancer is the fifth most frequent cause of cancer death world wide and most of these cancers occur in developing countries. The survival rate for SCC or ADCs of the oesophagus is equally poor, mainly due to their late detection and the poor efficacy of the therapy. A short review of the natural history of these cancers, and in particular the occurrence of genetic and cellular alterations associated with cancer progression, is presented and discussed in the context of the relevance to aetiology and pathogenesis. SCCs and ADCs show a distinct pattern of TP53 mutations, namely a high prevalence of G > A transitions at CpG sites in ADCs whereas in SCCs a higher prevalence of G to T transversions and mutations at A:T base pairs is present. In both types of cancers TP53 mutations occur very early and are followed by the accumulation of other genetic alterations during the process of oesophageal carcinogenesis. The value of these genetic alterations in assessing the multifocal monoclonal origin of oesophageal cancer is also addressed.