Corneal transplantation is the most commonly performed tissue transplant boasting over a century of history, science, and tradition. While favorable outcomes have been reported after penetrating keratoplasty, rejection remains a major cause of graft failure. The long-term survival rates of this relatively immunologically privileged tissue are only just comparable to those of vascularized organs. While corticosteroids treatment remains the gold standard for postoperative immunomodulation, other agents have been utilized in an ongoing effort to improve graft survival and patient outcomes. One of the most promising immunomodulatory substances whose immunosuppressive effect has revolutionized solid organ transplantation is cyclosporine (CsA). A calcineurin inhibitor, cyclosporine has been used as an immunosuppressive agent in corneal transplantation since the 1980's. Although some studies have shown beneficial effects of cyclosporine in both low- and high-risk corneal transplant patients the use of cyclosporine in rejection prophylaxis and treatment remain controversial and disputable. We herein present a literature review on the role of systemic cyclosporine in corneal transplantation.