The history of corneal transplantation reaches back over 150 years. Kissam performed one of the first penetrating keratoplasties when he transplanted a pig cornea onto a human in 1838. Only two interrupted sutures were used, and the surgery was performed without anesthesia! In retrospect, no one would be surprised to learn that the porcine corneal xenograft was rejected. Thirty years later, May transplanted rabbit corneal grafts to humans, but concluded that the failures in the first 24 attempts were the result of "imperfect technique and the inability to keep the eyes properly bandaged." The first documented report of a successful penetrating keratoplasty in a human subject was performed by Zirm in 1905. As we enter the new millennium, corneal transplantation remains the oldest, most common, and, arguably, the most successful form of solid tissue transplantation. In the United States alone, approximately 36,000 corneal transplants are performed each year. The success rate for corneal transplants is in excess of 90% in uncomplicated cases, even though HLA tissue typing is not performed and systemic immunosuppressive drugs are not administered. In spite of this extraordinary success, immune rejection remains the leading cause of corneal graft failure. Many inferences about the immunobiology of corneal graft rejection have been based on clinical observations; however, confirmation of these hypotheses requires prospective studies under controlled settings. The prudent use of animal models has fostered analytic studies on the immunobiology of corneal allografts without the complicating and confounding effects of topical steroids that are typically used on most keratoplasty patients. Although animal models of penetrating keratoplasty have been in use for almost a half-century, until recently, progress in understanding the immune mechanisms of corneal graft rejection has been slow. However, the widespread use of rodent models of orthotopic corneal transplantation has shed new light on the pathogenesis of corneal graft rejection.