Influenza A viruses (IAV) have caused more documented global pandemics in human history than any other pathogen. High pathogenicity avian influenza (HPAI) viruses belonging to the H5N1 subtype are a leading pandemic risk. Two decades after H5N1 “bird flu” became established in poultry in Southeast Asia, its descendants have resurged, setting off an H5N1 panzootic in wild birds that is fueled by (a) rapid intercontinental spread, reaching South America and Antarctica for the first time; (b) fast evolution via genomic reassortment; and (c) frequent spillover into terrestrial and marine mammals. The virus has sustained mammal-to-mammal transmission in multiple settings, including European fur farms, South American marine mammals, and US dairy cattle, raising questions about whether humans are next. Historically, swine are considered optimal intermediary hosts that help avian influenza viruses (AIV) adapt to mammals before jumping to humans. However, the altered ecology of H5N1 has opened the door to new evolutionary pathways. Could dairy cattle, farmed mink, or South American sea lions serve as new mammalian gateways to humans? Here we explore the molecular and ecological factors driving H5N1’s sudden expansion in host range and assess the likelihood of different zoonotic pathways leading to an H5N1 pandemic.