A variety of exciting and important new observations regarding the pathogenesis of nontypable H. influenzae infection have been made in the past decade. The interactions between mucin and OMPs show a high degree of specificity. Multiple adhesins have been identified on the bacterial surface. Colonization of the upper respiratory tract is a dynamic process. Immunodominant, antigenically heterogeneous OMPs are the targets of strain-specific immune responses, accounting in part for the recurrent nature of OM in otitis-prone children. The LOS of nontypable H. influenzae displays a remarkable degree of antigenic and phase variation and may be involved in molecular mimicry of host antigens. Finally nontypable H. influenzae not only lives on the mucosal surface but also clearly has been demonstrated to enter epithelial cells and remain viable in intracellular and intercellular locations in the human upper respiratory tract. These areas of investigation have important implications in understanding the pathogenesis of OM. Elucidating mechanisms of pathogenesis will be important in guiding development of novel ways to prevent OM.