Technical Abstract: Avian influenza (AI) viruses are a diverse group divided into 144 different subtypes based on different combinations of the 16 hemagglutinin and 9 neuraminidase subtypes, and two different pathotypes (low [LP] and high pathogenicity [HP]), based on lethality for the major poultry species, the chicken. However, other criteria are important in understanding the complex biology of AI viruses including host adaptation, transmissibility, infectivity, tissue tropism, and lesion and disease production. Overall, such pathobiological features vary with host species and virus strain. Experimentally, HPAI viruses typically produce a similar severe, systemic disease with high mortality in chickens and other galliforme birds. However, these same viruses usually produce no infection or only mild disease in domestic ducks and wild birds. Over the past decade, the emergent HPAI viruses have shifted to increased virulence for chickens as evident by shorter mean death times (MDT) and a greater propensity for massive replicate in vascular endothelial cells. Especially important, the Asia H5N1 HPAI viruses have changed from producing inconsistent respiratory infections in 2 week-old domestic ducks to some strains being highly lethal with virus in internal organs and brain. However, the high lethality for ducks is inversely related to age. The most recent Asian H5N1 HPAI viruses have infected some wild birds producing systemic infections and death. Across all bird species, the ability to produce severe disease and death is associated with high virus replication titers in the host, especially in specific tissues such as brain and heart.