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Respiratory viruses typically initiate infection in the nasal cavity, which serves as the primary site for viral entry. Subsequently, these pathogens replicate and may disseminate to other parts of the upper respiratory tract and lungs. While the majority of respiratory virus infections are confined to the nasal and upper respiratory regions, only a minority progress to severe pulmonary infections. However, the mechanisms of viral entry, exit, and spread within the nasal cavity, as well as the defensive responses of the nasal mucosal immune system, remain poorly understood. Here, we use an infection model based on primary human nasal epithelium, combined with omics approaches and mouse models, to address these important questions.