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The intestine is the largest lymphoid organ in the body by virtue of lymphocyte numbers and quantity of immunoglobulin produced. This is largely related to the enormous antigen load to which these cells are exposed on a daily basis. However, despite this, the mucosa-associated lymphoid tissue appears to be regulated by unique mechanisms, and this is reflected in specific phenomena (oral tolerance, controlled or physiologic inflammation) as well as unusual lymphoid populations (intra-epithelial lymphocytes) that respond to alternative pathways of activation. This, coupled with the existence of novel antigen-presenting cells (intestinal epithelial cells) sets the scene for distinct immune responses. It is these distinct regulatory factors that support immunosuppression or tolerance rather than active immunity at a site juxtaposed to the external environment. This review defines these novel interactions and suggests how alteration in normal function may result in allergic or inflammatory responses. A clearer understanding of mucosal immunoregulation may lead to new therapeutic approaches for these diseases.