This review summarizes four different kinds of therapeutic modalities for the treatment of devastating ocular surface disorders: the biologic approach, the immunologic approach, the microbiologic approach, and the combined and integrated approach. In the biologic approach, cultivated corneal epithelial stem cell transplantation, an advanced form of conventional limbal transplantation, is now considered the surgical modality of choice for limbal deficiency; autologous cultivated oral mucosal epithelial transplantation is also widely recognized. For the immunologic approach, immunosuppressive treatment and/or keratoepithelioplasty are very effective for treating peripheral corneal ulcers, including Mooren's ulcer. For the microbiologic approach, the management of commensal bacteria such as Propionibacterium acnes, and especially its elimination from the meibomian gland, is essential for the treatment of meibomitis-related keratoconjunctivitis. Finally, the combined approach is the only known means successfully to treat Stevens-Johnson syndrome because of the associated disordered innate immunity with corneal epithelial stem cell deficiency.