Twenty years ago in the South Chinese province of Guangdong the epizooty of highly pathogenic avian influenza (HPAI) H5N1 virus, which has laid the foundation of the largest epizooty in the contemporary history, has flashed. Hemagglutinin of prototype A/goose/Guangdong/1/1996 (H5N1) changing many times and generating new genetic subgroups participated in various reassortations; it still exists today. The present review is devoted to the retrospective analysis of HPAI/HSN1 evolution for the lasttwenty years in the territory of Eurasia, Africa and America. The basis for the discussion is ecological model according to which new genetic variants are formed in the migration pathways with close contacts between different bird populations and in the overwintering areas where the maximum values of the immune layer occur; amplification of virus variants occurs in nesting areas among juvenile populations. The updated system of designations of genetic groups introduced by WHO/OIE/FAO H5 Evolution Working Group in 2015 is used.