Human infections with highly pathogenic avian influenza (HPAI) H7N9 viruses have been detected in China, which raises concerns of a future pandemic, particularly if these viruses acquire efficient human-to-human transmissibility. However, the replication capacity, pathogenicity and transmissibility of human HPAI H7N9 isolates in mammals were unknown. Kawaoka and colleagues characterized a human HPAI H7N9 isolate and its recombinant derivatives that represent neuraminidase inhibitor-sensitive and -resistant subpopulations in vitro and in vivo. HPAI H7N9 viruses replicated efficiently in mice, ferrets and nonhuman primates and were more pathogenic than low-pathogenic H7N9 viruses in mammals. Moreover, HPAI H7N9 viruses transmit via respiratory droplets among ferrets and exhibit low sensitivity to neuraminidase inhibitors in mice. The findings suggest that the highly pathogenic H7N9 virus has pandemic potential and should be closely monitored.