This year marks the 100th anniversary of the deadliest event in human history. In 1918–1919, pandemic influenza appeared nearly simultaneously around the globe and caused extraordinary mortality (an estimated 50–100 million deaths) associated with unexpected clinical and epidemiological features. The descendants of the 1918 virus remain today; as endemic influenza viruses, they cause significant mortality each year.

Although the ability to predict influenza pandemics remains no better than it was a century ago, numerous scientific advances provide an important head start in limiting severe disease and death from both current and future influenza viruses: identification and substantial characterization of the natural history and pathogenesis of the 1918 causative virus itself, as well as hundreds of its viral descendants; development of moderately effective vaccines; improved diagnosis and treatment of influenza-associated pneumonia; and effective prevention and control measures.

Remaining challenges include development of vaccines eliciting significantly broader protection (against antigenically different influenza viruses) that can prevent or significantly downregulate viral replication; more complete characterization of natural history and pathogenesis emphasizing the protective role of mucosal immunity; and biomarkers of impending influenza-associated pneumonia.