Immunologic rejection is the main cause of corneal graft failure. If corneal transplantation is performed in a high-risk situation without the use of systemic immunosuppression, corneal graft failure has to be expected in over 50% of patients within the first postoperative year. The clonal expansion of graft-specific lymphocytes occurs in lymphoid tissues. As topical steroids do not reach the secondary lymphoid organs, and even systemic steroids do not interfere sufficiently with the clonal expansion of activated T cells, it is essential to administer systemic immunosuppressives in order to achieve clear graft survival. As corneal transplantation is not a life-saving procedure, the profile of side-effects is a central issue when choosing an immunosuppressive medication.