The human nasopharynx is the natural habitat and reservoir for Neisseria meningitidis and Haemophilus injluenzae type b (Bib). Meningococcal and Hib pathogenesis was studied in human nasopharyngeal tissue in organ culture. Inocula of ⩾106 meningococci or cfu of Hib were required for consistent production of infection in these cultures. By 24 hours meningococci and Hib grew to l()B-IOIO cfu/mL in culture supernatants, while 104–107 cfu per organ culture were tissue associated. These studies further indicated that nasopharyngeal mucus contains components that specifically bind Hib; that both meningococci and Hib cause cytotoxicity, resulting in breakdown of tight junctions of epithelial cells, sloughing of ciliated cells, and ciliostasis; that pili are the most important components mediating initial attachment of meningococci to nonciliated epithelial cells of the human nasopharynx; that Hib expresses both pilus and nonpilus adhesins that facilitate attachment to nonciliated cells; and that meningococci and Hib both invade the epithelial surface to reach the submucosa but do so by different routes. Meningococci and Hib have evolvedsuccessful, although divergent, mechanisms by which to infect the human nasopharynx.