In response to the ongoing threat to animal and human health posed by HPAI endemic in poultry, Asia (H5N1) and North America (H7N3) have revived efforts to reduce pandemic risk by disease control at the source and improved pandemic vaccines. Discovery of conserved neutralization epitopes in the HA, which mediate broad protection within and across HA subtypes have changed the paradigm of "broadly reactive" or "universal" vaccine design. Development of such vaccines would benefit from comparative antigenic analysis of viruses with increasing divergence within (and between) HA subtypes. A review of recent work to define the antigenic properties of HPAI viruses revealed data generated through an array of experimental approaches. This information has supported diagnostics and vaccine development for animal and human health. Further harmonization of analytical methods is needed to determine the antigenic relationships among multiple lineages of rapidly evolving HPAI viruses.