The gastrointestinal mucosa is in constant interaction with the luminal microenvironment, which contains commensal microbiota as well as a variety of bacterial, viral, and protozoan pathogens. A single layer of intestinal epithelial cells (IECs) as big as a tennis court (260-300m2) covers this large inner surface preventing uncontrolled dissemination of pathogens within host tissues (Nagler-Anderson, 2001). The intestine has a highly adaptable host defense system in which the intestinal epithelium and the mucosal immune system tightly cooperate through chemokines to facilitate barrier function while allowing the development of immunity. Dendritic cells (DCs) and macrophages play an important role in the immune defense of the gut, particularly in sampling pathogens and bacteria (Neutra et al., 1996; Kelsall et al., 2002; Uhlig and Powrie, 2003). Interactions of antigen-presenting DCs with antigen-specific T-lymphocytes trigger the induction of adaptive immune responses and are also critical for the control of tissue inflammation and the maintenance of immune tolerance (Kelsall et al., 2002; Steinman et al., 2003). Evidence from mouse models of inflammatory bowel disease (IBD) indicates that dysregulation of antigen recognition and processing of intestinal microbiota are common disease mechanisms (Podolsky, 2002). Furthermore, mutations in proteins involved in pathogen pattern recognition have been associated with Crohn's disease (CD) (Hugot et al., 2001; Ogura et al., 2001). Chemokines and their receptors orchestrate the intercellular communication required to maintain the complex architecture of immune compartments in the intestine at multiple levels. Homeostatic chemokines are responsible for a steady-state turnover of lymphocytes and DCs in the lamina propria and Peyer's patches (PPs) and their migration to and from mesenteric lymph nodes (MLNs). A particular role of epithelial cell-derived chemokines has been established for the direction of DCs, T-cells, and B-cells within these immune-cell compartments of the intestine. While a number of trafficking signals are ubiquitously shared among leukocyte populations that respond to inflammation throughout the body, intestine-specific chemokine signals begin to emerge that are linked to the intrinsic functional programs and subspecifications of leukocytes in the mucosal immune system.