SARS-CoV-2 enters the epithelial cells in the upper respiratory tract to begin replication and infection. Nasal airways are composed of stratified multiciliated epithelial cells and mucus-producing goblet cells. How the virus overcomes this mucus barrier to infect the nasal epithelium is not completely understood. In this new study, Wu et al. show that first, SARS-CoV-2 binds the ACE2 receptor present on airway motile cilia. Cilia then mediate the transport of the virus across the underlying mucus–mucin protective barrier. Once SARS-CoV-2 accesses the basal cell body, it manipulates the host cell machinery to induce the activation of p21-activated kinases 1 (PAK1) and 4 (PAK4). Such reprogramming results in the elongation and branching of microvilli, which enable the virus to reach the nasal airways and disperse via mucus flow. Finally, the authors show that Omicron variants bind with higher affinity to the cilia and show accelerated entry compared with other variants, which explains their higher transmissibility. In sum, SARS-CoV-2 interaction with cilia and microvilli is key for viral replication and spread in the airways.