The lung, in order to facilitate gas exchange, represents the largest epithelial surface area of the body in contact with the external environment. As normal respiration occurs, the upper and lower airways are repeatedly exposed to a multitude of airborne particles and microorganisms. Since these agents are frequently deposited on the surface of the respiratory tract, an elaborate system of defense mechanisms is in place to maintain the sterility of the lung. Innate defenses are primarily responsible for the elimination of bacterial organisms from the alveolus. Early bacterial clearance is mediated by a dual phagocytic system involving both alveolar macrophages and polymorphonuclear leukocytes. The recruitment and activation of inflammatory cells at a site of infection involves the orchestrated expression of leukocyte and vascular adhesion molecules, as well as the establishment of chemotactic gradients via the generation of proinflammatory cytokines and chemokines. Immunologic manipulation of innate immunity may serve as an important adjuvant therapy in the treatment of both immunocompromised and immunocompetent patients with severe lung infections. As the complexities of the host-pathogen interaction are further dissected and elucidated, it is likely that the therapeutic benefits from these approaches will be realized.