The "Spanish influenza" pandemic of 1918 was the most devastating influenza epidemic reported in history and killed >30 million people worldwide. The factors contributing to the severe pathogenicity of this influenza virus are of great interest, because avian influenza viruses circulating today pose the threat of a new pandemic if they develop sustained human-to-human transmissibility. Recent characterization of the 1918 virus has illuminated which determinants may be the cause of virulence. Here, we wish to shed light on what has been learned to date about the 1918 virus with regard to pathogenicity and transmissibility, to supplement our understanding of the determinants of human virulence and transmission of pandemic influenza viruses. Monitoring the sequences of avian influenza viruses for genetic changes and diversity may help us to predict the risks that these viruses pose of causing a new pandemic. © 2006 by the Infectious Diseases Society of America. All rights reserved.