Avian influenza is a highly contagious respiratory viral infection of birds caused by influenza A viruses (AIVs). Most AIVs are designated as low pathogenicity viruses and are maintained by wild waterfowl and sea birds. Only AIVs of the H5 and H7 subtypes have shown the capability to produce highly pathogenic avian influenza (HPAI) causing severe multi-organ systemic infection associated to high morbidity and mortality rates in poultry. Since the early 2000s, HPAI A(H5Nx) viruses of the goose/Guangdong lineage (gs/GD) have not only affected domestic poultry, but also wild birds, which have facilitated the intercontinental spread of that lineage through migratory routes. This contributed to the constant evolution of these viruses through re-assortment, resulting in the emergence of various genetic clades and subclades. Globally, HPAI A(H5Nx) viruses have caused the death of more than 633 million poultry, including both direct mortality from infection and indirect losses due to culling, and a sharp increase in the number of affected wild birds and mammalian species, highlighting their impact on the food industry and biodiversity preservation.