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Particle size dictates where aerosolized pathogens deposit in the respiratory tract, thereafter the pathogens potential to cause disease is influenced by tissue tropism, clearance kinetics and the host immunological response. This interplay brings pathogens into contact with a range of tissues spanning the respiratory tract and associated anatomical structures. In animal models, differential deposition within the respiratory tract influences infection kinetics for numerous select agents. Greater numbers of pathogens are required to infect the upper (URT) compared with the lower respiratory tract (LRT), and in comparison the URT infections are protracted with reduced mortality. Pathogenesis in the URT is characterized by infection of the URT lymphoid tissues, cervical lymphadenopathy and septicemia, closely resembling reported human infections of the URT. The olfactory, gastrointestinal, and ophthalmic systems are also infected in a pathogen-dependent manner. The relevant literature is reviewed with respect to particle size and infection of the URT in animal models and humans.