In¯uenza A virus initiated worldwide epidemics (pandemics) in 1918, 1957, 1968 and 1977. A revised calculation of the 1918±1919 pandemic estimates that 40 million persons died and 500 million were infected. The mortalities in 1957 and 1968 were nearly 6 million. Biological and genetic characteristics of the causative agents of the more recent pandemics, have been well studied but little is known about the causative agent of the Great Pandemic in 1918. Genetic characterisation of the 1918 virus has been achieved by sourcing virus RNA from formalin ®xed lung samples or by exhuming frozen victims of the outbreak from Arctic regions. Initial analysis of the HA gene from two USA sources indicates a virus related to swine and human in¯uenza with no base insertion at the HA1-HA2 cleavage junction which, at least in avian in¯uenza A, characterises high virulence. Important unanswered questions are whether the 1918 virus spread pantropically perhaps to include the brain and hence cause encephalitis including the later lethargic forms, or whether infection was con®ned to the respiratory tract. Re-examination of reports of respiratory disease in England and France in 1916±1917 may indicate a non-Spanish origin of the pandemic and a period of 2 years for the virus to be seeded worldwide. In contrast the other two pandemic viruses in 1957 and 1968 appeared to originate in Asia. New anti-neuraminidase drugs in conjunction with amantadine and novel developments with in¯uenza vaccines would be expected to ameliorate the disease in a future pandemic.