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The intestinal mucosa functions is an immunologic organ that plays a major role in the development of oral tolerance and host-defense mechanisms. Antigens must cross the intestinal epithelium in a controlled manner to interact with dendritic antigen-presenting cells, because bacteria or their products are a primary risk factor for the development of intestinal inflammation. Therefore, the regulation of the intestinal epithelial cell barrier is central to the development of intestinal immunity and inflammation, but the involved mechanisms are largely unknown. Intestinal barrier function relies on the formation of tight junctions at the apical contact areas of intestinal epithelial cells. Tight junctions have a highly dynamic structure whose permeability, assembly, or disassembly can be regulated by a variety of cellular and metabolic mediators, including cytokines, which have major functions in the immune system. Immune modulators control tight junction dependent intestinal barrier function during development, wound healing, and pathologic processes such as cancer, infection, and chronic inflammation.