Influenza is an acute respiratory illness, caused by influenza A, B, and C viruses, that occurs in local outbreaks or seasonal epidemics. Clinical illness follows a short incubation period and presentation ranges from asymptomatic to fulminant, depending on the characteristics of both the virus and the individual host. Influenza A viruses can also cause sporadic infections or spread worldwide in a pandemic when novel strains emerge in the human population from an animal host. New approaches to influenza prevention and treatment for management of both seasonal influenza epidemics and pandemics are desirable. In this Seminar, we discuss the clinical presentation, transmission, diagnosis, management, and prevention of seasonal influenza infection. We also review the animal-human interface of influenza, with a focus on current pandemic threats.