The earliest reported case of the H5N1 virus affecting humans occurred alongside an H5N1 epidemic in non-humans (epizootic outbreak) in Hong Kong poultry. The entire poultry population was then culled to prevent the disease going on to affect other animal species (panzootic outbreak).

However, the disease still spread and the World Health organization announced in December 2009 that it had affected a total of 447 people and claimed 263 lives.

Researchers soon discovered that H5N1 is easily spread between birds meaning the virus could potentially spread across the world. Although H5N1 can mutate to form strains that are infective to species not previously thought to be affected by the virus, not all of those strains are infective to humans. The virus preferentially binds to a galactose receptor present in the avian respiratory tract. These receptors are virtually nonexistent in humans and occur only in the alveoli, deep within the lungs, meaning the virus cannot easily be transmitted through the usual routes such as coughing and sneezing.
 

The disease is generally spread through the movement of birds and poultry products, as well as through the use of infected manure as feed or fertilizer. Humans who have caught the virus have generally done so through contact with chickens that had been infected by other poultry or waterfowl. Geese, wild ducks and swans often carry the H5N1 without displaying any symptoms themselves. These migrating waterfowl can carry the infection far and wide, transmitting it among domestic poultry and increasing the risk of transmission to humans.

The virus has also mutated into a variety of strains, each with different pathogenic profiles that may or may not be infective to one or multiple species. For example, the H5N1 virus isolates found in Hong Kong in 1997 and 2001 were not easily and consititently transmitted between birds. It was in 2002 that new isolates started to appear that could cause severe neurological damage and death. This marked the emergence of Genotype Z, which included mutated strains of previous pathogenic H5N1 genotypes that infected the Chinese bird population in 1996 and humans in Hong Kong in 1997. Genotype Z, which is endemic in birds in Southeast Asia has formed two new strains that are spreading across the globe and can affect humans. Birds can also shed the virus for a longer period before they die, therefore increasing the window of time for transmission.