Advances in molecular biology have revealed a consistent set of genetic alterations that may correspond to multistep tumor development. The pathogenesis of adenoma and differentiated adenocarcinoma of the stomach are reviewed from a genetic perspective with reference to the colorectal adenoma-carcinoma sequence. The sequential accumulation of genetic alterations characteristic of the colorectal adenoma-carcinoma sequence does not occur between adenoma and differentiated adenocarcinoma of the stomach, although adenomatous polyposis coll (APC) mutation in adenoma, and p53 mutation and loss of heterozygosity (LOH) of DCC (deleted in colorectal cancer) gene in carcinoma are prevalent genetic alterations. Allelotype, LOH and microsatellite analyses have revealed several chromosomal regions of deletion, as well as genetic instability, that accumulate during the development and progression of differentiated adenocarcinomas. However, these alterations are rarely found in adenomas of the stomach. These findings suggest that the adenoma-carcinoma sequence is relatively rare in gastric carcinogenesis, and that most differentiated adenocarcinomas of the stomach develop through a de novo pathway.