One of the distinguishing features of the 1918 pandemic is the occurrence of massive, potentially detrimental, activation of the innate immune system in critically ill patients. Whether this reflects an intrinsic capacity of the virus to induce an exaggerated inflammatory responses or its remarkable ability to reproduce in vivo is still open to debate. Tremendous progress has recently been made in our understanding of innate immune responses to influenza infection and it is now time to translate this knowledge into therapeutic strategies, particularly in view of the possible occurrence of future outbreaks caused by virulent strains.