Homeostasis of the corneal surface is maintained by epithelial stem cells localized in the limbus. Multiple intrinsic factors or external injuries can destroy the delicate microenvironment of limbal epithelial stem cells causing a state which is termed limbal stem cell deficiency (LSCD). In such cases, re-epithelialization of the cornea is drastically impeded and conjunctival epithelium starts to extend beyond the limbus and to invade the corneal surface. In partial LSCD, a superficial keratectomy combined with an amniotic membrane is advised and helpful to restore an intact, healthy ocular surface. In complete LSCD, stem cell transplantation is the only curative option. Before any reconstruction, causative factors and comorbidities should be eliminated or at least optimized. In cases of unilateral LSCD, stem cells can be obtained from the contralateral eye. Advanced surgical and cultivation techniques pursue a gentle, tissue-saving procedure of harvesting a limbal biopsy from the only healthy functioning eye. Patients with bilateral involvement can be treated with allogeneic tissue, but will require long-term systemic immunosuppressive therapy. Another newer option is the use of autologous, but noncorneal epithelial cells as a tissue source, e.g., buccal mucosa. Future studies will focus on the further development of cellular expansion and/or the establishment of new alternative sources for replacing limbal epithelial stem cells.