Influenza A viruses (IAVs) are among the most versatile viruses, in terms of host range, pathogenesis, route of transmission, transmissibility efficiency, and evolutionary dynamics. Several IAVs are recognized pathogens of a wide range of avian and mammalian species. On the one hand, they cause mild or asymptomatic infections of the intestinal tract in wild water birds, their natural reservoirs, resulting in annual epidemic cycles fueled by IAV fecal-oral transmission in watershed habitats. On the other hand, they may cause disease manifestations in poultry and mammalian species, including humans, upon sporadic cross-species transmission and during self-limiting outbreaks or large-scale airborne epidemics. In these spillover host species, clinical signs and symptoms range from inapparent to severe and often fatal respiratory and extra-respiratory conditions. A feature of IAVs in domestic spill-over hosts and humans is their ability to adapt to these new species to eventually be maintained independently of new introductions from their natural host reservoirs. In humans, IAVs of animal origin can be the precursors of pandemic influenza viruses. These pandemic viruses eventually evolve into seasonal influenza viruses that cause recurring epidemics of seasonal influenza. Through their versatile nature, IAVs are a striking example of the flexible nature of zoonotic threats and of the richness of avenues zoonotic pathogens can take to burden public health.