The H5N1 highly pathogenic avian influenza virus (HPAIV) of clade 2.3.4.4b emerged in Europe during 2020-2021 and rapidly spread worldwide via migratory birds, causing outbreaks in poultry, wild birds, and wildlife. Sporadic cases of human infection, likely resulting from close contact with infected animals, have been reported. In March 2024, clinical signs (e.g., reduced feed intake, altered milk quality, and decreased milk production) were observed in dairy cattle on a farm in Texas, USA, where H5N1 HPAIV was subsequently isolated. By December 2024, infections had been reported in dairy cattle across 15 states in the USA. Cases of infection have also been documented in cats near affected farms and in humans suspected of exposure through contact with infected cattle or chickens that acquired the virus from cattle. These developments have raised concerns about the potential for further transmission of H5N1 HPAIV to humans. In recent studies, H5N1 HPAIV strains isolated from cattle and humans exhibited high pathogenicity in mice and ferrets. Furthermore, ferret studies showed efficient transmission via respiratory droplets. This unprecedented spread of H5N1 HPAIV among mammals raises concerns about the emergence of a virus capable of efficient human-to-human transmission via respiratory droplets. Continued global surveillance of infection dynamics is essential to mitigate this potential public health threat.