The intestinal mucosa contains the largest reservoir of macrophages in the body. Intestinal macrophages are derived from circulating blood monocytes that localize exclusively to the lamina propria, where they lose certain surface antigens and receptors, including CD11a-c, CD14 and FcRI-III, but retain HLA-DR, CD13 and TLR3, 5-9. The absence of CD11a and b on human intestinal macrophages helps distinguish these cells from intestinal myeloid dendritic cells. The distinct phenotype of human intestinal macrophages, reflected by the absence of CX3CR1, challenges direct comparison between human and mouse mucosal macrophages based on single common surface antigens. Resident human intestinal macrophages are potently down-regulated for the production of regulatory cytokines such as IL-10 and all inflammatory cytokines (inflammation anergy) through stromal TGF-mediated Smad signaling and NF-B inactivation, but retain powerful phagocytic and microbicidal activity. Thus, human intestinal macrophages clear local apoptotic cells and provide host defense against microbes that breach the epithelium in a non-inflammatory manner, thereby contributing to mucosal homeostasis.