Highly pathogenic avian influenza A (H5N1) continues to circulate globally in avian and mammalian species. Since its emergence in 1997, over 1000 confirmed human infections with H5N1 have been reported, with a case-fatality rate of approximately 50%. In recent years, H5N1 clade 2.3.4.4b viruses have caused extensive outbreaks in wild birds and poultry, resulting in the culling of hundreds of millions of birds. This influenza lineage has also expanded into mammalian hosts, including widespread outbreaks in American dairy cattle and over 70 confirmed human infections in the USA, with two fatalities. The rapid global dissemination and expanding host range of H5N1 clade 2.3.4.4b have raised genuine concerns about its pandemic potential.