Michael Worobey, Professor, Ecology and Evolutionary Biology, The University of Arizona The Spanish influenza pandemic of 1918 was the most intense outbreak of disease in human history. It killed upwards of 50 million people (most in a six-week period) casting a long shadow of fear and mystery: nearly a century later, scientists have been unable to explain why, unlike all other influenza outbreaks, it killed young adults in huge numbers. I will describe how analyses of large numbers of influenza virus genomes are revealing the pathway traveled by the genes of this virus before it exploded in 1918. What emerges is a surprising tale with many players and plot lines, in which echoes of prior pandemics, imprinted in the immune responses of those alive in 1918, set the stage for the catastrophe. I will also discuss how resolving the mysteries of 1918 could help to prevent future pandemics and to control seasonal influenza, which quietly kills millions more every decade.