Otitis media is a major cause of morbidity in 80% of all children less than 3 years of age and often goes undiagnosed in the general population. There is evidence to suggest that the incidence of otitis media is increasing. The major cause of otitis media is infection of the middle ear with microbes from the nasopharynx. The anatomical orientation of the eustachian tube, in association with a number of risk factors, predisposes infants and young children to the infection. Bacteria are responsible for approximately 70% of cases of acute otitis media, withStreptococcus pneumoniae, nontypeableHaemophilus influenzaeandMoraxella catarrhalispredominating as the causative agents. The respiratory viruses, respiratory syncytial virus, rhinovirus, parainfluenza and influenza, account for 30% of acute otitis media cases. Over the past decade, there has been a profound increase in the reported resistance to antibiotics, which, with increased disease burden, has focussed attention on vaccine development for otitis media. A polymicrobial formulation containing antigens from all major pathogens would have the greatest potential to deliver a sustained reduction in the disease burden globally. The disappointing outcomes for otitis media seen with the polysaccharide pneumococcal conjugate vaccine have raised major challenges for the vaccination strategy. Clearly, more knowledge is required concerning immune mechanisms in the middle ear, as well as vaccine formulations containing antigens that are more representative of the polymicrobial nature of the disease. Antigens that have been extensively tested in animal models are now available for testing in human subjects.