Corneal transplantation is a sight-restorative procedure but its success is limited by irreversible graft rejection, which accounts for up to 50 per cent of failures. The normal eye is an immune-privileged site. Multiple mechanisms maintain ocular privilege, including the blood-eye barrier, the lack of blood vessels and lymphatics in the normal cornea, the relative paucity of mature antigen-presenting cells in the central cornea, the presence of immunomodulatory factors in ocular fluids, and the constitutive expressive of CD95L (Fas ligand) within the eye. However, privilege can be eroded by the sequelae of inflammation and neovascularization. Corneal graft rejection in humans is currently suppressed with topical glucocorticosteroids, which are moderately effective. Systemically administered immunosuppressive therapy is of limited efficacy and may be accompanied by unacceptable morbidity. Alternative therapies are needed to improve outcomes. Corneal graft rejection is primarily a cell-mediated response controlled by the CD4+ T cell, and thus CD4 and costimulatory molecule blockade are appealing targets for new therapeutic interventions. A number of monoclonal antibodies have shown promise as immunosuppressants to prolong corneal graft survival in experimental animal models, and may eventually prove to be useful adjuncts to corticosteroids.