The mucosal surface of the body is exposed to a vast array of exogenous antigens and microorganisms. Epithelial cells evoke minimal immune response to food ingredients and commensal bacteria, while they release an array of antimicrobial peptides and CXC chemokines in response to bacterial invasion or inflammatory stimuli. The mucosal antigens are transported from the gut lumen to organized lymphoid follicles by specialized epithelial M cells residing in follicle-associated epithelium (FAE). An alternative pathway of antigen uptake with neonatal Fc receptor (FcRn) is also reported. Furthermore, intestinal dendritic cells underneath epithelium directly take up luminal antigens, where epithelial fractalkine expression plays a critical role in the guidance of dendrite extrusion. Epithelial cells express polymeric Ig receptor (pIgR) that is essential for the luminal secretion of dimeric IgA produced in the lamina propria. Furthermore, soluble factors released by mucosal epithelial cells condition dendritic cells, which in turn promote Th2 response. These multiple lines of evidence clearly suggest the significant role of epithelial cells at the front line of mucosal immune defense.