AbstractDespite the immune‐privilege of the cornea, transplant rejection remains the leading cause for graft failure following penetrating keratoplasty. This is particularly true in the high‐risk recipients, e.g. following previous graft failure due to rejection, infectious keratitis and vascularized corneas. Several strategies including local and systemic immune modulatory agents are currently used to increase the success rate of high‐risk corneal grafts. Although corticosteroids are still a major component of our immunopharmacological armentarium, they might be supplemented by other more specific immunomodulating agents. The spectrum includes agents such as methotrexate calcineurin inhibitors affecting T‐cells (cyclosporin A, FK506), mycophenolate mofetil and more selective monoclonal antibodies directed against T‐cell subpopulations and other targets. New options may include JAK kinase and anti‐Rho directed approaches that remain under investigation.In addition, preoperative MHC and non‐MHC antigens matching have been investigated as strategy to reduce immune‐mediated graft rejection however, results still remain controversial. In order to better evaluate the risks and benefit of these approaches the properties of established and forthcoming options are presented.