Cholesteatoma of the middle ear 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 invading the surrounding tissue structures with mainly clinical manifestations of ear discharge and hearing loss, it can produce a series of intracranial and extracranial complications such as vertigo, peripheral facial paralysis, intracranial infections and even life-threatening. Surgery remains the only available treatment now. The etiology and pathogenesis of middle ear cholesteatoma are not entirely clear. With the development of whole exon sequencing (WES) and other new generation sequencing technology, some breakthroughs have been made in the genetics of middle ear cholesteatoma. In recent years, there are more and more studies on the family aggregation and gene mutation of cholesteatoma, and the relationship between cholesteatoma and syndrome. This article will review the above for the sake of the non-surgical treatment and drug development of middle ear cholesteatoma.