The Spanish influenza pandemic of 1918-19 was one of three pandemics in the last century. It was exceptional among human influenza pandemics for the severity of disease experienced by victims of the pandemic, particularly among healthy young adults. Following the recent reconstruction of the complete 1918 virus, examination of host responses and pathological outcomes in animal models of infection has provided insight into the mechanism of viral pathogenesis. The reconstructed 1918 virus is highly virulent in the macaque, mouse and ferret models and replicates to high levels throughout the respiratory tract. Infection results in extensive lung injury, including severe hemorrhage and edema and destruction of the respiratory epithelium. Host responses in the macaque and mouse include rapid and sustained activation of proinflammatory cytokines and chemokines that are linked to the extensive infiltration of infected tissue by neutrophils and activated macrophages. These responses likely exacerbate tissue damage and contribute to the lethal outcome of infection. With recent concerns about the potential for a pandemic caused by the highly pathogenic avian H5N1 influenza (HPAI H5N1) virus a better understanding of the mechanisms used by virulent viruses to cause disease will be essential for the development and effective use of vaccines and anti-viral therapeutics.