The mucosal epithelium presents a formidable structural and chemical barrier to ill-intentioned microbes, which gain entry into the lamina propria (1) by dendritic cells, (2) through disrupted or injured epithelium, (3) between or through intact epithelial cells, and (4) through M cells. In noninflamed lamina propria, macrophages phagocytose and kill microbes without an inflammatory response. In the present of inflammation and dysregulated mucosal homeostasis, newly recruited monocyte-derived macrophages (and other innate host defense cells) generate transforming growth factor-β (TGF-β) and chemokines to recruit monocytes and other leukocyte populations to contain the infection. Microbes and/or their products are transported by dendritic cells in the lymphatics to draining lymph nodes where they induce an adaptive immune response. Failed clearance of the microbe and/or an inability to restore homeostatic regulation because of genetic and environmental factors can perpetuate inflammation locally and/or systemically (illustration by Lydia Kibiuk, NIH).