Highly pathogenic avian H5N1 influenza A viruses occasionally infect humans, but currently do not transmit efficiently among humans. The viral haemagglutinin (HA) protein is a known host-range determinant as it mediates virus binding to host-specific cellular receptors1, 2, 3. Here we assess the molecular changes in HA that would allow a virus possessing subtype H5 HA to be transmissible among mammals.