Influenza A viruses pose a constant threat to humans, because zoonotic viral transmissions can cause severe disease and give rise to devastating pandemics. Currently, it is not possible to predict the pandemic potential of avian influenza A viruses. We now describe a new mouse model suitable for risk assessment. It is based on the finding that innate restriction factors represent effective species barriers that need to be overcome by viruses trying to invade a human host. In mice, innate immune control of influenza viruses is mediated by the interferon-regulated Mx1 gene. The MX1 orthologue of humans (encoding MxA protein) provides broad resistance to influenza and other viruses in cell culture systems. MxA is targeting the nucleoprotein of influenza A viruses which encapsidates the viral genome and is pivotal to virus replication. Influenza A viruses that successfully established stable lineages in humans acquired adaptive mutations in the nucleoprotein that allow partial MxA escape in cell culture experiments. Our new mouse strain lacks functional endogenous Mx genes but instead carries the human MX1 locus as transgene. Our transgenic mice were largely resistant to highly pathogenic avian H5 and H7 influenza A viruses, but were almost as susceptible to infection with influenza viruses of human origin as non-transgenic littermates. We further demonstrate that an engineered avian H7N7 influenza virus carrying a nucleoprotein with signature mutations typically found in human virus isolates was more virulent in transgenic mice than the parental virus. These findings illustrate that a few amino acid changes in the viral nucleoprotein can mediate escape from MxA restriction in vivo. They further suggest that equivalent mutations need to be acquired by any emerging influenza A viruses before they can spread efficiently in the human population.