At the height of World War I, the human population was assaulted by a powerful, but very small, foreign agent that rapidly appeared seemingly from nowhere. Ultimately identified as the ‘‘Spanish flu’’, this agent wreaked havoc on anyone in its path. Prostrating vast numbers of victims worldwide with severe pneumonia, which often progressed to a fatal outcome, the ‘‘Spanish flu’’caused an estimated 20–50 million deaths worldwide [1]. The resultant 1918 pandemic was one of the most formidable foes faced by humankind. In this brief review, we discuss some recent insights into the pathogenicity of its causative agent, the 1918 pandemic influenza virus.