The epithelium plays a crucial role as an interface of adaptive responses and innate responses to prevent invasion of inhaled environmental pathogens. This paper summarizes the recent progress in our understanding of the regulation of defense mechanisms in the upper airway epithelium under normal and viral-infected conditions. Among respiratory viruses, respiratory syncytial virus (RSV) is the major infectious agent that causes serious respiratory tract inflammation in infants. RSV upregulates a receptor for Streptococcus pneumoniae. In our study, we found that clarithromycin and fosfomycin significantly suppressed RSV-induced adhesion of S. pneumonia in the airway epithelium. Moreover, these macrolide antibiotics are known to exert immunomodulatory activity by reducing pro-inflammatory cytokine and interferon production. Meanwhile, we found that biological products such as curcumin and humulone have protective effects against RSV and prevent the disruption of the epithelial barrier by viral infections in human nasal mucosa. Therefore, they are useful for both the prevention and treatment of respiratory viral infections.