In both infants and adults, infections with non-typeable Haemophilus influenzae (NTHI) results in morbidity and mortality. NTHI strains are the leading cause of bacterial otitis media infections (both acute and recurrent) in young children and are also responsible for chronic obstructive pulmonary disease (COPD) exacerbations in current and former smokers. The realization that NTHI causes serious infections in humans has generated interest in the study of the pathogenesis associated with this bacterium and also stimulated considerable efforts towards the evaluation of candidate vaccines that will elicit protective immunity. As NTHI is exclusively a human pathogen and has not been associated with any diseases in other mammals, special efforts have been necessary to establish animal models of NTHI infection to generate useful data on the pathogenesis of infection and efficacy of potential vaccines. This article provides a brief summary of the role of NTHI in disease and the work that has been accomplished by us and several other investigators. Copyright © 2011 S. Karger AG, Basel.