Antigens entering the body through the mucosal surface are screened by a highly developed immune system comprised not only of traditional lymphoid cells but also epithelial cells, fibroblasts, and antigen-presenting cells (APCs). For example, in the intestinal tract, gut-associated lymphoid tissue (GALT) is tolerant to the approx 400 separate commensal strains residing mainly in the colon, but also retains the capacity to detect and remove virulent bacteria before they infect systemically. This review summarizes recent work characterizing the molecular mechanisms involved in acute and chronic intestinal inflammation. We will also describe a natural murine pathogen, Citrobacter rodentium, which is being used to explore the host response to enteric pathogens and the resulting immunopathology.