Pandemics of influenza emerge from the aquatic bird reservoir, adapt to humans, modify their severity, and cause seasonal influenza. The catastrophic Spanish H1N1 virus may have obtained all of its eight gene segments from the avian reservoir, whereas the Asian H2N2 and the Hong Kong H3N2 pandemics emerged by reassortment between the circulating human virus and an avian H2 or H3 donor. Of the 16 hemagglutinin subtypes, the H2, H5, H6, H7, and H9 viruses are considered to have pandemic potential. While this chapter focuses on the evolution of the Asian highly pathogenic (HP) H5N1 influenza virus, other subtypes are also considered. The unique features of the HP H5N1 viruses that have devastated the domestic poultry of Eurasia are discussed. Although they transmit poorly to humans, they continue to kill more than 60% of infected persons. It is unknown whether HP H5N1 will acquire human pandemic status; if it does not, another subtype eventually will do so, for a future influenza pandemic is inevitable.