Rejection is the leading cause of corneal graft failure, induced by loss of the so-called eye immune privilege. Prevention of graft rejection with immunosuppressive therapy is then necessary. Topical corticosteroids are currently the gold standard, and steroids are the only treatment for acute rejection episodes. Steroids are nonspecific immunosuppressive agents, and they can induce glaucoma, cataract, infections, and epithelial defects. Cyclosporin has a specific effect, because it inhibits interleukin-2 transcription and, consequently, the specific activation of T lymphocytes. When cyclosporin is given orally, it effectively prevents graft rejection in high-risk recipients, but it may induce severe side effects (i.e., systemic hypertension, kidney deficiency, and malignant tumor induction). When cyclosporin is given topically, it can effectively replace steroids in case of dexamethasone-induced glaucoma and graft infection, but it can also induce serious corneal epithelial defects. Cyclosporin is not a treatment for acute rejection episodes. Mycophenolate mofetil and FK 506 are promising drugs, but currently they cannot be used routinely to prevent corneal graft rejection.