Specialized epithelial M cells, a phenotype that occurs only in the epithelium over organized lymphoid follicles, deliver samples of foreign material by transepithelial transport from the lumen to organized lymphoid tissues within the mucosa of the small and large intestines. Mounting evidence indicates that a complex interplay of mucosal lymphoid cells and luminal microorganisms with epithelial cells underlies differentiation of the M cell phenotype. The cellular and molecular features of M cells that promote adherence and transport of antigens and microorganisms are crucial for the design of mucosal vaccines and for understanding the strategies that pathogens use to exploit this pathway.