The mucosal immune system is equipped with unique innate and acquired defense mechanisms which provide a first line of protection against ingested and inhaled infectious agents. Peyer's patches (PPs) and nasopharynx-associated lymphoid tissue (NALT) have been shown to be important inductive sites for the initiation of the acquired phase of antigen-specific immune responses. In addition, the mucosal innate immune system acts as both a physical and an immunological boundary, playing a key role in the sensing and eliminating of pathogens and in the creating of symbiosis. The mucus layer covering the mucosal epithelium acts as a first physical and biochemical barrier. An additional layer of physical protection against microorganisms is provided by a tightly interlaced cell-to-cell network of epithelial cells and intraepithelial lymphocytes. Various antimicrobial peptides produced by the epithelium and secreted into the mucosal lumen can directly kill the invading pathogenic bacteria. Finally, Toll-like receptors (TLRs) associated with the mucosal compartment have been shown to recognize the pathogen-associated molecular patterns (PAMPs) of a variety of pathogenic and commensal microorganisms. Therefore, a greater understanding of the immunological progression from mucosal innate to acquired immune systems should facilitate the development of new generation of mucosal vaccines to prevent and control infectious diseases.