Chronic otitis media is the major reason for middle ear surgery. Epidemiological studies have revealed high heritability of persistent or recurrent middle ear inflammation. The genetic basis of chronic otitis media is complex, but a number of methods can be used to interrogate this complexity. The most promising method is the identification of genetic mutant mouse models, which may highlight genes to test for association with human disease, and enable pathobiology to be explored. Such an approach has suggested that the gene FBXO11 is associated with susceptibility to otitis media in man, and has also suggested that hypoxia signaling is an important component of the chronically inflamed middle ear. We discuss future research strategies in this field.