Avian influenza (H5N1), also known as H5N1 avian influenza, is a highly pathogenic influenza that has infected many chickens and humans in the world, especially in countries Asians. The global spread of the H5N1 epidemic itself occurs due to undetected H5N1-infected migratory waterfowl moving seasonally, large quantities of poultry, and illegal trade in developing countries such as Southeast Asia, which is difficult to control and eradicate causing intercontinental spread. The first outbreak occurred in Guangdong Province, China, in a farmed goose, and human infections were first reported the following year, 1997, in Hong Kong with 6 deaths out of 18 cases . Avian influenza viruses (H5N1) belong to the Orthomyxovirus type A family and are characterized by its glycoproteins which are hemagglutinin (HA) and neuraminidase (NA). Migratory waterfowl, especially mallard ducks, are predicted to be natural reservoirs of influenza A H5N1 virus because all 16 hemagglutinin (HA) subtypes and 9 neuraminidase (NA) subtypes of influenza A virus are isolated from these hosts and even mallard ducks can be silent hosts who show only few signs of illness. Influenza A viruses can be transmitted from the natural host to many species such as pigs, tigers, leopards, cats, eagles and humans. The modes of transmission of H5N1 are expected to be the live bird market (LBM), illegal trade, and transportation of illegal poultry or exotic birds. Based on the cumulative number of human cases from WHO, there are 565 cases including 331 deaths in 15 countries from the first wave of H5N1 in 2003 until 2011, with Indonesia as the highest incidence of human cases of H5N1 among the countries infected with H5N1. Some control measures have been applied to eradicate H5N1, such as burial, single-dose compound H5N1 vaccine has been tested as safe and immunogenic in adults. In conclusion, H5N1 is a highly pathogenic and lethal avian influenza virus, susceptible to and transmissible to many species, including humans. Although human-to-human transmission has not yet been confirmed as possible, this first outbreak should provide an important lesson on responding to sick poultry and applying hygiene rules. Vaccination in both poultry and humans is extremely important to prevent recurrence of the H5N1 epidemic. Incentives and compensation should be given to farmers because in rural areas poultry becomes the main source of income and food. With incentives and aid from the government to improve living standards, there will be less backyard poultry and illegal poultry; therefore, control measures can be successfully implemented to eradicate the existing H5N1 virus.