The epithelium of the respiratory tract forms a large surface area that maintains intimate contact with the environment. Through the act of breathing, this mucosal surface encounters an array of pathogens and toxic particulates. In response to these challenges many strategies have evolved to protect the host. These include the barrier functions of the epithelium, cough, mucociliary clearance, resident professional phagocytes, and the secretion of a number of proteins and peptides with host defense functions. Thus, the surface and submucosal gland epithelium of the conducting airways is a constitutive primary participant in innate immunity. In addition, this tissue may serve the function of a secondary amplifier of innate immune responses following neurohumoral input, stimulation with cytokines from cells such as alveolar macrophages, or engagement of pattern recognition receptors. Here, we provide an overview of the airway epithelium's role in pulmonary innate immunity, especially in the context of bacterial and viral infections, emphasizing findings from human cells and selected animal models. We also provide examples of human disease states caused by impaired epithelial defenses in the lung.