The first known human infection with a highly pathogenic H5N1 influenza A virus appeared in China in 1997. Between 2003 and 2017, the WHO documented an additional 862 human cases, mainly from southeast Asia and Egypt, with a mean annual case fatality rate of 56%. By 2006, the susceptibility of cats to severe respiratory and neurologic disease became apparent. Scientists raised concerns regarding the potential for domestic cats to transmit novel pathogenic strains to humans. But after 2006, reports of new H5N1 infections in companion animals dwindled, and human cases fell after 2016. In 2021, H5N1 clade 2.3.4.4b viruses suddenly appeared in Europe and spread rapidly to the Americas, wreaking havoc on wildlife and crippling the poultry and dairy industries. Between 2022 and 2025, dozens of domestic cats died, most often following raw food consumption. Unease regarding the transmission potential of pets resurfaced. Although most human infections in the Americas were mild and associated with poultry or dairy contact, the recent detection of genotype D1.1 in association with severe illness or death is cause for concern. Genotype D1.1 has now also been detected in dairy cattle and domestic cats. Reports of H5N1 clade 2.3.2.1a viruses in India suggest a new potential threat. Successful control of H5N1 infections is strongly dependent on a One Health approach. Small animal veterinarians play a key role in this approach through recognition of cases and education of pet owners, thus preserving the human-animal bond.