Influenza viruses are significant human respiratory pathogens that cause both seasonal and pandemic infections. The 1918 pandemic, the worst on record, killed approximately 50 million people worldwide. The histopathology of fatal influenza pneumonias over the past 120 years is reviewed, showing that the spectrum of pathologic changes in the 1918 pandemic is not significantly different from other pandemics or seasonal influenza. The 1918 pandemic was characterized by a higher case fatality rate and an unusual age distribution of deaths, with many previously healthy young adults succumbing to fatal influenza. The review also discusses the pathology of influenza A viruses, the biology of influenza viruses, and the clinical course of the disease. Influenza A viruses replicate in both the upper and lower respiratory tract, with virus recoverable from both areas. The pathology of influenza includes multifocal destruction and desquamation of the epithelium in the trachea and bronchi, edema, congestion, and mononuclear inflammatory cell infiltrates. Influenza pneumonia is characterized by capillary and small vessel thromboses, interstitial edema, inflammatory infiltrates, hyaline membranes, acute intraalveolar edema, and diffuse alveolar damage. Secondary bacterial pneumonias are common and complicate the histopathologic appearance. The review also discusses the pathology of H5N1 highly pathogenic avian influenza infections and experimental animal models of influenza virus infection.Influenza viruses are significant human respiratory pathogens that cause both seasonal and pandemic infections. The 1918 pandemic, the worst on record, killed approximately 50 million people worldwide. The histopathology of fatal influenza pneumonias over the past 120 years is reviewed, showing that the spectrum of pathologic changes in the 1918 pandemic is not significantly different from other pandemics or seasonal influenza. The 1918 pandemic was characterized by a higher case fatality rate and an unusual age distribution of deaths, with many previously healthy young adults succumbing to fatal influenza. The review also discusses the pathology of influenza A viruses, the biology of influenza viruses, and the clinical course of the disease. Influenza A viruses replicate in both the upper and lower respiratory tract, with virus recoverable from both areas. The pathology of influenza includes multifocal destruction and desquamation of the epithelium in the trachea and bronchi, edema, congestion, and mononuclear inflammatory cell infiltrates. Influenza pneumonia is characterized by capillary and small vessel thromboses, interstitial edema, inflammatory infiltrates, hyaline membranes, acute intraalveolar edema, and diffuse alveolar damage. Secondary bacterial pneumonias are common and complicate the histopathologic appearance. The review also discusses the pathology of H5N1 highly pathogenic avian influenza infections and experimental animal models of influenza virus infection.