Respiratory tissues are bombarded by billions of particles daily. If allowed to accumulate, these particles can cause injury, inflammation, or infection, and thus may significantly disrupt airflow and gas exchange. Mucociliary defense, a primary mechanism for protecting host tissues, operates through the coordinated functions of mucus and cilia that trap and eliminate inhaled materials. Mucociliary function is also required for the elimination of endogenous cells and debris. Although defense is necessarily robust, it is also tightly regulated to minimize physiologic disruption of the host. Indeed, mucociliary dysfunction contributes to the pathogenesis of many lung diseases—including asthma, chronic obstructive pulmonary disease, pulmonary fibrosis, and cystic fibrosis—in which airflow limitation, inflammation, persistent tissue injury, and structural remodeling occur. Here, we highlight recent advances in cilia and mucin biology, the importance of well-controlled mucociliary interactions, and the need to better understand how these regulate innate barrier and immune defense.