The highly pathogenic avian influenza (HPAI) H5N1 virus, particularly clade 2.3.4.4b, is currently causing a panzootic. The threat of its incursion into mainland Australia is escalating, especially following its detection in Antarctica and recently on Australia´s sub-Antarctic territory, Heard Island. Comprehensive research on this emerging risk remains limited, partly due to ongoing rapid genomic mutations and evolving epidemiological dynamics. This review provides an in-depth analysis of clade 2.3.4.4b H5N1 and highlights critical knowledge gaps that must be addressed to mitigate the potential threat to mainland Australia.