Cholesteatoma is a mass formed by the keratinizing squamous epithelium of the tympanic cavity and/or mastoid and subepithelial connective tissue and keratin debris, with/without a surrounding inflammatory reaction. When it invades surrounding structures, intracranial and extracranial complications, such as vertigo, peripheral facial paralysis, intracranial infections and even death can happen. Surgery remains the only available treatment now. The etiology and pathogenesis of middle ear cholesteatoma are not entirely clear, with the development of a new sequencing technology such as whole exome sequencing, the genetic research of middle ear cholesteatoma has made some breakthrough progress. In recent years, there are more and more studies on the family aggregation of cholesteatoma, mutations and its relationship to the syndrome. This article will review the above for the sake of the non-surgical treatment and drug development of middle ear cholesteatoma.