The clinical picture of COVID-19 varies widely. Many SARS-CoV-2-infected individuals have upper respiratory symptoms only, indicating that local immunity can constrain viral pathology to the nasopharynx. A study in Cell by Ziegler et al. investigated early intrinsic immune responses by single-cell RNA-seq of nasopharyngeal swabs from 58 individuals, including 35 who were recently diagnosed with COVID-19. In patients with mild-to-moderate disease, epithelial cells expressed antiviral and interferon-responsive genes. These responses were muted in individuals with severe COVID-19, despite equivalent viral loads. Severe disease was also characterized by the mucosal recruitment of highly inflammatory myeloid populations. The authors mapped viral tropism to specific epithelial cell subsets and defined host pathways that were linked with susceptibility or resistance. Overall, their study suggests that failed nasal epithelial antiviral immunity underlies severe COVID-19 and that host responses in the nasal mucosa are an essential determinant of the overall disease trajectory.