Otitis media (OM) is the most common disease in children in the United States, with about $5 billion spent each year in direct and indirect costs. OM is the number one reason for pediatric antibiotic usage and surgery, although treatment options are limited. Numerous studies have established the high heritability of OM and a genetic contribution to OM pathogenesis. Candidate gene studies have highlighted the roles of inflammation, mucin secretion, and pathogen recognition, but this approach is unable to identify novel pathways to target for treatment or screening purposes. Here, we review the current literature on agnostic approaches to discover novel genes and pathways involved in OM pathogenesis.