This review, published in Pathogens, provides an updated synthesis of the emergence, molecular evolution, and epidemiological trajectory of highly pathogenic avian influenza (HPAI) viruses of the goose/Guangdong (GsGD) H5 lineage. Among the multiple clades that evolved since the original detection in 1996, clade 2.3.4.4b is emphasized as the most consequential due to its extensive global dissemination, adaptability across ecosystems, and unprecedented expansion of host range into mammals, including livestock. The review stresses that the recent detection of cow-to-cow and cow-to-human transmission represents a paradigm shift in avian influenza epidemiology and underlines the urgent need for strengthened surveillance and preparedness. The review is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license: https://creativecommons.org/licenses/by/4.0/