Every day, we breathe in more than 10,000 L of air that contains a variety of air pollutants that can pose negative consequences to lung health. The respiratory mucosa formed by the airway epithelium is the first point of contact for air pollution in the lung, functioning as a mechanical and immunologic barrier. Under normal circumstances, airway epithelial cells connected by tight junctions secrete mucus, airway surface lining fluid, host defense peptides, and antioxidants and express innate immune pattern recognition receptors to respond to inhaled foreign substances and pathogens. Under conditions of air pollution exposure, the defenses of the airway epithelium are compromised by reductions in barrier function, impaired host defense to pathogens, and exaggerated inflammatory responses. Central to the mechanical and immunologic changes induced by air pollution are activation of redox-sensitive pathways and a role for antioxidants in normalizing these negative effects. Genetic variants in genes important in epithelial cell function and phenotype contribute to a diversity of responses to air pollution in the population at the individual and group levels and suggest a need for personalized approaches to attenuate the respiratory mucosal immune responses to air pollution.