H5Nx viruses remain a threat to human health. Over the past few years, the H5Nx clade 2.3.4.4b has rapidly spread to 6 continents, leading to massive avian and mammalian host deaths. In late March 2024, H5N1 was first identified in lactating dairy cows in the United States and has spread to 16 states, affected hundreds of herds, and caused over 50 known human infections. In this review, we discuss the origins of 2.3.4.4b H5N1 viruses and how they are evolving to better infect mammals, with an emphasis on receptor-binding characteristics. Understanding changes in receptor binding and mutations in the viral genome that allow for sustained spread in mammals can inform public health measures and prevent future influenza virus epidemics and pandemics.