The mammalian gastric mucosa and its glands are both of endodermal origin and together represent a tight barrier to the outside world. Here, two types of gastric units form homeostatic systems, i.e. fundic and antral units, showing continual bi-directional self-renewal via differentiation from stem and progenitor cells. This review describes recent developments concerning the different populations of gastric stem cells as well as the various gastric epithelial cell types and their self-renewal. Parietal cells, as the organizing centers of fundic units, are particularly important in regulating differentiation of the mucous neck-zymogenic cell lineage. Here, the morphogen Sonic hedgehog (SHH) plays a key role. Furthermore, dysregulated gastric self-renewal occurs in specific diseased states. For example, the TFF2/spasmolytic polypeptide expressing metaplasia (SPEM) is the result of a dysregulated trans-differentiation of the mucous neck-zymogenic cell lineage and SPEM can even evolve to intestinal metaplasia. Both metaplasic states represent premalignant conditions for the "intestinal" type of gastric cancer. Dysregulated differentiation also occurs in the course of chronic inflammation with SHH being a key target for inflammatory processes.