The first highly pathogenic H5N1 emerged in 1959 on a chicken farm in Scotland. The ancestor of the strains presently circulating was isolated in 1996 from a domestic goose in China. Since 1997, more than 900 severe human infections have been reported. However, in nearly thirty years, H5N1 has failed to adapt to human-to-human transmission. At present the abundant circulation in various animal species, including mammals, increases the possibility of reassortments of new pandemic strains. Particularly alarming was the recent report of H5N1 infection among U.S. dairy cattle. A strong international effort from a global health perspective addressed to limit the avian strains circulation and to improve the preparedness for a new pandemic is urgently needed.