Gao and her colleagues recently reported in this journal the increasing genetic diversity of novel H5N6 avian influenza viruses (AIVs) persisting in Guangdong Province of China, which posed the serious risk of persistence and dissemination in Southern China. Since its emergence in 2013, highly pathogenic avian influenza (HPAI) H5N6 virus had been circulating in domestic poultry in mainland China and in sporadically infected humans, thereby posing significant threats to public health. Strikingly, the isolation of novel HPAI H5N6 viruses from domestic poultry and migratory birds was documented as causing continuous outbreaks in numerous countries including South Korea, Japan, and mainland China during late 2016 to mid 2017.