Dynamic host-pathogen relationships take place at the mucosal epithelia of the respiratory and gastrointestinal tracts. The nasal mucosa harbors a rich microbial community that transitions to a relatively sparse microbiome in the lung; in contrast, pathogenic interactions in the gut must override an abundant commensal flora. In all these sites, pathogens exploit normal host cell processes to their advantage. Co-opting the host's machinery implies that diverse pathogens target similar receptors and that common themes of pathogenesis can be elucidated. This is especially true of the respiratory tract and may form the basis of medical interventions. Virtually all mucosal pathogens adhere to and then invade the epithelial cells of their target organ. The details of these interactions are discussed in the framework of not only cell biology, but also the host response. The innate and adaptive immune responses are as critical to eliminating the pathogens as to causing symptoms secondary to inflammation.