Mucosal host immunity in the respiratory tract can probably be manipulated to better improve defense against microbes and other antigens or particulates that cause infection and respiratory illness. An evolving strategy is to target the extensive network of dendritic cells in the lungs, especially dendritic cells located in the airway epithelium, which are super antigen-presenting cells that can initiate specific T-lymphocyte immune responses. Also, dendritic cells can elaborate cytokines such as interleukin 12 which drive other components of the immune response including antibody production. However, dendritic cells can be counter-regulated by inhibitory cytokines or certain microbes that create a dynamic interplay. This review emphasizes human studies and relevant animal models that provide a framework for future planning of experimental approaches to enhancing antimicrobial immunity and respiratory host defense.