Advances have been made in identifying the gastric epithelial stem cells and their immediate descendents which act as uncommitted or committed progenitors giving rise to cell lineages producing the various contents of the gastric juice and several hormones. New research suggests that these epithelial stem/progenitor cells also play an important role in the development of gastric cancer. In this review, we summarize results of examining three genetically manipulated mouse models in which the biological features and differentiation program of the gastric stem/progenitor cells were altered by three different approaches: 1) knockout of the trefoil factor 1 gene which is expressed initially in the partially committed pre-pit cell progenitors known to produce both mucus- and acid-secreting cell lineages, 2) expression of Simian virus 40 large T antigen gene in the acid-secreting parietal cell lineage, and 3) ablation of the parietal cells by using the attenuated diphtheria toxin A fragment. Systematic analysis of these animal models provided some clues to the role played by gastric stem/progenitor cells during carcinogenesis and to the cellular origin of gastric cancer.