Recent work on H5N1 influenza A virus, in which strains have been genetically engineered to enable aerosol transmission between ferrets, has been criticized for potentially being dangerous. Here, Langlois et al. present an approach that could be used to improve the biosafety of such gain-of-function influenza virus experiments. Endogenous host microRNAs (miRNAs) have been shown to suppress the expression of viral genes, so the authors reasoned that modifying the viral genome to contain target sites for miRNAs present in humans and mice but absent in ferrets would block potential transmission to humans. miR-192 was identified as a candidate miRNA, as it is expressed specifically by human and mouse lung epithelial cells, but not ferret cells. Importantly, incorporation of the miR-192 target site into the viral genome did not interfere with transmission between ferrets, but it did attenuate pathogenicity in mice, which did not succumb to infection.