Cells of the gastric mucosa undergo constant renewal, the rate depending on the health of the tissue (inflammation, ulceration, carcinogenesis). While much attention has been focused on the mechanism of mucosal damage and the pathogenesis of ulceration, there has recently been the recognition that elucidation of the nature of the gastric stem cell lineages as well as the regulators of phenotype expression of this system may yield considerable biological information as well as open the door to the identification of areas of therapeutic relevance. Chimeric and X-inactivation studies in mice and humans demonstrate that each region of the gastric mucosa is morphologically diverse (antrum is different to the fundus), with its own repertoire of cell types and glandular structures. The current evidence suggests that a single stem cell in every gastric gland indirectly gives rise to a clone of all differentiated cells, by production of committed progenitor cells. It is also this multipotential cell that produces new crypts by crypt fission, repairs entire crypts when damaged, and gives rise to the ulcerassociated cell lineage and gastric carcinomas. It is likely that this stem cell occupies a niche in the isthmus composed of mesenchymal cells and extracellular matrix factors, which regulates the function of the cell via mesenchymal-epithelial cross talk. The molecular events (IGF-signaling) that regulate the development of the gastric gland in the mice have begun to be understood. Ultimately, the identification of these pathways will play an important role in identifying new molecular targets for the treatment of gastric disease.