The emergence of lethal, virulent variants of the influenza A virus, such as the one that caused the 1918 'flu pandemic that killed 50 million people, presumably arise from specific mutations. In the Early Edition of Proceedings of the National Academy of Sciences, Brown et al. describe studies designed to investigate the molecular basis of viral virulence. They performed serial passaging in mouse lungs to select for highly virulent strains. The adaptation of the H3N2 prototype clinical isolate, A/HK/1/68, resulted in a virulent variant which is caused by a group of 11 mutations. The virulance mutations involve nuclear localization signals and sites of protein and RNA interactions. Three mutations are also found in the virulent human H5N1 isolate A/HK/156/97. Thus, viral adaptation experiments give insights into viral virulence mechanisms and convergent viral evolution.