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This report examines the current state of preparedness for pandemics caused by “high-impact respiratory pathogens”—that is, pathogens with the potential for widespread transmission and high observed mortality. Were a high-impact respiratory pathogen to emerge, either naturally or as the result of accidental or deliberate release, it would likely have significant public health, economic, social, and political consequences. Novel high-impact respiratory pathogens have a combination of qualities that contribute to their potential to initiate a pandemic. The combined possibilities of short incubation periods and asymptomatic spread can result in very small windows for interrupting transmission, making such an outbreak difficult to contain. The potential for high-impact respiratory pathogens to affect many countries at once will likely require international approaches different from those that have typically occurred in geographically limited events, such as the ongoing Ebola crisis in Democratic Republic of the Congo (DRC).