In this study, Blanchard et al. characterize a novel antiviral approach that uses the CRISPR-Cas system (Cas13a-crRNA) designed to cleave specific RNA sequences present in influenza or SARS-CoV-2 infections that results in inhibited viral replication. The authors first developed and characterized the individual components (Cas13 delivery via mRNA and strain-specific CRISPR RNA (crRNA) guides) against multiple influenza strains and demonstrated RNA knockdown in vitro and following nebulizer-based delivery in an in vivo mouse infection model. By tailoring the crRNA sequence against the SARS-CoV-2 replicase and nucleocapsid genes, the authors successfully demonstrated positive results as a prophylactic treatment for SARS-CoV-2 in a hamster infection model.