The highly pathogenic Asian H5N1 influenza virus that was first detected in Guangdong in the People's Republic of China (China) in 1996 is unique in having spread to humans and other mammalian species. To date, this virus has not consistently transmitted between any mammalian species but the continued spread and evolution of these viruses in domestic poultry across Eurasia presents a continuing pandemic threat. These viruses have caused devastation in domestic poultry and have killed over 60% of infected humans. The H5N1 viruses are unique in having evolved into multiple clades and subclades by reassortment with other influenza viruses in the epicentre of southern China, and accumulation of point mutations has resulted in antigenic differences between the clades. Three waves of spread have occurred, wave one to East Asia and Southeast Asia, wave two through Qinghai Lake, China, to Europe, India and Africa, and wave three to Southeast Asia again. This paper deals with the molecular epidemiology of the evolution of the multiplicity of H5N1 clades. The continuing evolution of these H5N1 viruses and the possible establishment of secondary epicentres in Indonesia, Egypt and Nigeria present a continuing threat to poultry and people globally.