Barrier epithelia, especially airway epithelial cells, are persistently exposed to micro-organisms and environmental factors. To protect the host from these microbial challenges, many immune strategies have evolved. The airway epithelium participates in the critical innate immune response through the secretion of immune effectors such as mucin, antimicrobial peptides (AMP), and reactive oxygen species (ROS) to entrap or kill invading microbes. In addition, airway epithelial cells can act as mediators connecting innate and adaptive immunity by producing various cytokines and chemokines. Here, we present an overview of the role of mucosal immunity in airway epithelium, emphasizing the framework of bacterial and viral infections along with regulatory mechanisms of immune effectors in human cells and selected animal models. We also describe pathophysiological roles for immune effectors in human airway disease.