 The Spanish influenza pandemic of 1918 to 1919, which caused almost equals 50 million deaths worldwide, remains an ominous warning to public health. Many questions about its origins, its unusual epidemiologic features, and the basis of its pathogenicity remain unanswered. Understanding the 1918 pandemic and its implications for future pandemics requires careful experimentation and in-depth historical analysis. This article was authored by Jeffrey K. Taubenberger and David M. Morins.