The widespread circulation of highly pathogenic avian influenza (HPAI) H5N1 clade 2.3.4.4b in wild birds in North America since late 2021 has resulted in multiple outbreaks in commercial and backyard poultry leading to major economic losses. Since the emergence of the virus in North America, multiple reassortment events have led to the emergence of many new variant genotypes that have been isolated from wild birds, with several viruses spilling over into poultry and other terrestrial and aquatic mammalian hosts. Notably, the most recent emerging HPAI H5N1 reassortant genotype B3.13 spilled over into dairy cattle (Bos taurus), resulting in unprecedented efficient transmission of the virus in this species, the first case of sustained transmission in a mammalian species. The transmission pathways involved in the spread of the virus from its first detection in Texas to several other states are complex. However, movement of subclinically infected cattle likely played a major role in virus spread. Infection in dairy cattle is characterized by the virus´s tropism for milk-secreting cells in the mammary gland, leading to high viral load and shedding in milk. Replication of the virus in milk-secreting cells results in destruction of infected cells leading to severe viral mastitis, which is characterized by marked changes in milk quality (altered consistency and color) and pronounced decline in milk production by clinically affected animals. Here, we provide an overview of the HPAI H5N1 panzootic virus and discuss its host range and the current knowledge of its pathogenesis in the new bovine host.