Keratin is a strong, fibrous protein that coats the skin, male genitalia and some tissues in the mouth and female genitalia. Keratin protects the host by providing a barrier against primary herpes simplex virus infection. We postulate that keratin may also hinder the host by protecting the virus from effective immune responses such as those present on mucosal surfaces, enabling recurrent lesions to preferentially develop within keratinized tissues at mucocutaneous junctions. The natural history of infection supports the importance of preventing infection in keratinized tissues for developing an effective herpes simplex virus vaccine, since potent immunity on mucosal surfaces may be inadequate to protect keratinized tissues.