The 1918 influenza A virus pandemic caused a death toll of 40 to approximately 50 million. Currently, because of the widespread dissemination of the avian influenza virus (H5N1), there is a high risk of another pandemic. Avian species are the natural hosts for numerous subtypes of influenza A viruses; however, the highly pathogenic avian influenza virus (HPAI) is not only extremely lethal to domestic avian species but also can infect humans and cause death. This review discusses why the avian influenza virus is considered the most likely candidate for the first flu pandemic of the 21st century.