Traditionally, the epithelial lining of the gastrointestinal tract has been one of the few organs about which there has been little argument concerning its nature as a stem cell-based lineage system. However, the detailed mechanisms of how these cells function is not as fully elaborated as those for hematopoietic stem cells of the bone marrow. Indeed, only functional and positional assays for these cells have been useful investigationally, and it is only recently that a few antigens have been tentatively identified as markers of “stem cell-ness.” What is meant by the term “stem cell” in this context? Classically, it is defined as a proliferative cell that necessarily produces at least one stem cell when dividing (i.e., self renewal) and gives rise to more differentiated daughter cells that then populate the various cells that line the rest of the intestinal crypt and villous in the small intestine (i.e., pleuripotency). In the gastrointestinal tract, Potten et al. have further extended the definition to include the ability to alter its self-maintenance probability to ensure expansion of stem cell numbers in the event of severe injury, so called “clonogenic capacity.” While markers for these cells have been lacking, careful labeling and tracking studies have indicated that the stem cell of the intestinal crypts can be identified precisely by cell position counted from the base of the crypt. Moreover, since all cells of the crypt lining derive from the stem cells, their relative positions toward the top of the crypt or villous relate to their age and to their differentiation state. These differentiated cells fall into common subtypes (columnar cells, mucin-secreting/goblet cells, endocrine cells and, in the small intestine, Paneth cells) and less common subtypes (caveolated cells and M cells). The subepithelial myofibroblasts of the intestinal crypts form a syncytium, which lines the crypts and extends through the lamina propria, merging with pericytes of the blood vessels. These cells influence or even regulate stem cell behavior, by secreted factors (e.g., hepatocyte growth factor, TGFkeratinocyte growth factor) and by direct cell-cell contact.