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The 1918 to 1919 H1N1 influenza pandemic is among the most deadly events in recorded human history, having killed an estimated 50 to 100 million persons. Recent H5N1 avian influenza epizootics associated with sporadic human fatalities have heightened concern that a new influenza pandemic, one at least as lethal as that of 1918, could be developing. In early 2009, a novel pandemic H1N1 influenza virus appeared, but it has not exhibited unusually high pathogenicity. Nevertheless, because this virus spreads globally, some scientists predict that mutations will increase its lethality. Therefore, to accurately predict, plan, and respond to current and future influenza pandemics, we must first better-understand the events and experiences of 1918.Although the entire genome of the 1918 influenza virus has been sequenced, many questions about the pandemic it caused remain unanswered. In this review, we discuss the origin of the 1918 pandemic influenza virus, the pandemic's unusual epidemiologic features and the causes and demographic patterns of fatality, and how this information should impact our response to the current 2009 H1N1 pandemic and future pandemics. After 92 yrs of research, fundamental questions about influenza pandemics remain unanswered. Thus, we must remain vigilant and use the knowledge we have gained from 1918 and other influenza pandemics to direct targeted research and pandemic influenza preparedness planning, emphasizing prevention, containment, and treatment.