Influenza A viruses pose a substantial threat to the human population whether by purposeful manipulation and release or by the natural process of interspecies transmissions from animal reservoirs. The challenge with preparing for these events with vaccination strategies is that the best forms of protective immunity target the most variable of the viral proteins, hemagglutinin. Add to this even just the natural extent of variation in this protein and the challenges to vaccinologists become great. Progress must be made in the area of streamlining the conventional vaccine approaches, but also in further defining and testing more conserved protective antigens. Within the context of biodefense, the issue will be to reach a balance where some of the diversity of influenza viruses can be encompassed within a vaccine while maintaining an acceptable level of efficacy.