Previous studies have shown that the highly pathogenic avian influenza A virus H5N1 can transmit between ferrets via the airborne route following the acquisition of several mutations. Fouchier and colleagues now show that a minimal set of five mutations is sufficient for this phenotype. Two of the mutations altered the preference of viral haemagglutinin (HA) from avian to mammalian receptors, another substitution increased HA thermostability and the final two mutations (which occurred in the RNA polymerase proteins PB1 and PB2) together increased viral transcription and replication. These adaptive mutations emerged rapidly during viral passage in ferrets and became dominant. As airborne transmissibility is a major contributing factor to the pandemic potential of pathogens, these data should aid surveillance programmes that assess the public health risks of H5N1.