Respiratory infection with Francisella tularensis is the deadliest form of disease and represents the most likely route to be used by bioterrorists. Although mucosal surfaces represent the first line of defense against respiratory tularemia, and in fact, against the great majority of human pathogens, little is known about protective immunity at these sites. The objective of this chapter is to review recent data examining the importance of various pulmonary immune mechanisms in defense against F. tularensis infection and to evaluate potential strategies for induction of protective lung immunity. Aerosol and intranasal mouse infection models have yielded essentially equivalent results and have implicated an important role for Th1-type immune responses in protection, including IFN-gamma, TNF-alpha, and IL-12. The cells responsible for protection in the lung are not well-characterized but NK cells are an early target for activation after infection although it appears that CD8 T cells might be most critical for host resistance. In addition, it is becoming increasingly clear that antibodies can provide prophylactic and therapeutic protection against pulmonary infection but only in the presence of active cell-mediated immunity. In fact, in vitro exposure of resting macrophages to antibody-coated bacteria in the absence of IFN-gamma can actually enhance infection. Although various immune mechanisms can be shown to be important for protection against attenuated strains such as LVS, the real challenge for the future is to design efficacious approaches to prevent disease by highly virulent strains such as SchuS4.