The unprecedented spread of highly pathogenic H5N1 viruses since 1996 has had public health and scientific entities scrambling to prepare for a possible pandemic. Central to many of these efforts has been the development of vaccines. As the viruses have continued to spread, however, they have continued to diversify genetically, complicating vaccine strain selection. The key to successful vaccine design is understanding the cross-reactivity between these genetically distinct H5N1 strains. Studies conducted to date show encouraging amounts of cross-reaction and cross-protection between various H5N1 strains, although our ability to predict one based upon the other is poor. Understanding the targets and mechanisms behind this cross-protection should be a key focus of pandemic preparedness.