The occurrence and the relevance in squamous cell carcinomas (SCC) and Barrett's adenocarcinomas (ADC) of genetic alterations, namely mutations in the p53 gene, allelic loss at various chromosomal loci and altered expression of genes involved in the regulation of cell proliferation, are described and discussed with reference to the etiology and pathogenesis of esophageal cancers. Mutations in the p53 gene occur in both SSC and ADC with a frequency of up to approximately 80%, although with a strikingly different pattern of mutations. In ADC, a very high frequency of G > A transitions at CpG dinucleotides was observed, whereas in SCC, mutations at A:T base pairs was comparatively high. In addition, in SCC, the frequency of p53 mutations was related to tobacco smoking. These data therefore indicated that such mutation analysis could provide valuable insight into the etiology of this cancer. It is also apparent that the genetic alterations involving genes other than p53 are also present in the natural history of esophageal cancer. The significance of these genetic changes as well as alterations of expression of cell cycle regulatory genes in esophageal carcinogenesis is briefly discussed.