Corneal allotransplantation is highly successful in the short term, but much less successful in the longer term. Many corneal grafts in recipients with corneal neovascularization or the sequelae of ocular inflammation undergo irreversible rejection, despite topical immunosuppression with glucocorticosteroids. Sensitization to cornea-derived alloantigen proceeds by both direct and indirect routes, but the anatomic location of sensitization remains unclear. Multiple and redundant mechanisms operate in the effector phase of corneal graft rejection, which is largely cell-mediated rather than antibody-mediated. Human leukocyte antigen matching may improve outcomes in high-risk patients but systemic immunosuppression is frequently ineffective and is seldom used.