Influenza viruses continue to pose a major global public health problem. There is a need to better understand the pathogenicity and transmission of pandemic influenza viruses so that we may develop improved methods for their prevention and control. Reconstruction of the 1918 virus and studies elucidating the exceptional virulence and transmissibility of the virus are providing exciting new insights into this devastating pandemic strain. The primary approach has been to reconstruct and analyze recombinant viruses, in which genes of the 1918 virus are replaced with genes of contemporary influenza viruses of lesser virulence. This review highlights the current status of the field and discusses the molecular determinants of the 1918 pandemic virus that may have contributed to its virulence and spread. Identifying the exact genes responsible for the high virulence of the 1918 virus will be an important step toward understanding virulent influenza strains and will allow the world to better prepare for and respond to future influenza pandemics.