The gastrointestinal epithelial layer hosts a large population of lymphoid cells called intraepithelial lymphocytes (iIELs), and locates adjacent to the intestinal lumen and mucosal barrier. These lymphocytes are continuously exposed to orally encountered antigens via intestinal epithelial cells (iECs), and have unique phenotypical and functional features compared with T cells from other lymphoid compartments. CD3-positive T cells are major populations of iIELs and gamma delta TCR- and CD8-positive sub-populations are dominant. A close functional relationship between iIELs and iECs has been shown, and they play an important role in the immune surveillance of epithelial compartments and regulation of mucosal immune defenses to exogenous and endogenous antigens in the intestine. It is interesting that gamma delta TCR-positive iIELs regulate the generation and differentiation of iECs. The immunoregulatory functions of iIELs in the mucosal immune systems are also implicated in the oral tolerance. Basic research for the clinical trials of the oral tolerance to the treatment of autoimmune and allergic diseases recently has gegun.