Highly pathogenic avian influenza (HPAI) H5N1, which has caused severe disease in poultry since 1996, has become panzootic in wild birds and recently has spread to dairy cattle and other mammalian species in the United States. Although few human cases have been reported, devastating HPAI H5N1 poultry outbreaks and massive dieoffs in wild birds and in some mammals raise concern about pandemic potential. Surveillance, early detection, public health interventions, farm biosecurity measures, and next-generation vaccines may reduce the risk of a future HPAI H5N1 pandemic.