In October 2020, a novel clade 2.3.4.4b H5N1 highly pathogenic avian influenza virus (HPAIV) was first detected in wild ducks in the Netherlands and rapidly disseminated globally, causing unprecedented outbreaks among wild birds, poultry, and an expanding range of mammalian hosts. By June 2025, over 1,000 confirmed H5N1 infections had been reported in dairy cattle across 17 U.S. states, with epidemiological evidence pointing to interstate transmission via asymptomatic or pre-symptomatic animals. More than 70 human infections have also been reported in the U.S., including one fatality, and genomic data revealed close similarity between viruses isolated from humans and infected cattle. The widespread host range and repeated spillover events suggest increasing mammalian adaptation of the virus, with profound implications for wildlife ecology, food security, and global public health.