Influenza A viruses all originate from aquatic birds, which are their natural reservoir. From this vast, ever-present and global source they are able to cross the species barrier and infect a variety of hosts, including humans. Progressive viral adaptation of avian-origin viruses to novel hosts including domesticated birds, pigs, horses, dogs, or humans may result in widespread viral circulation and in the establishment of endemic viruses in a given population. In humans, influenza A infections usually are caused by endemic seasonal viruses and much less frequently by animal influenza viruses that cross the species barrier. A few times each century, some of the animal viruses also gain the capacity to sustain transmission among human populations, resulting in a pandemic. By definition, any emerging pandemic virus will be different antigenically from both human vaccine virus strains and contemporary human viruses, and so the human population will be immunologically naïve to a significant degree to the new virus before it spreads widely. To date, only viruses of the H1, H2, and H3 subtypes are known to have caused pandemics and establish subsequent global circulation.