Gastric cancer is the second leading cause of cancer deaths worldwide. Although the link between Helicobacter pylori infection and gastric cancer is well established, little is known about the early development and detection of this malignant disease. Cancer is the disease of epithelia and recently, it has been suggested that some cancers originate in adult stem cells. Advances have been made in identifying the gastric epithelial stem cells and their immediate descendents, which act as progenitors giving rise to mucus-, acid-, pepsinogen-, and hormone-secreting cell lineages. Analyses of some genetically manipulated animal models in which the proliferation and differentiation program of the gastric stem/progenitor cells was altered by different approaches have provided some clues to the cellular origin of gastric cancer. Despite the challenges and the similarity between gastric epithelial progenitors and their differentiation program in mice and humans, it remains to be determined whether observations made in genetically engineered mice are also applicable to humans.