The major findings regarding corneal allograft rejection in experimental animals are reviewed. The principal anatomic and biological feature of the cornea that determines the immunologic privilege of this tissue is its avascularity. The surgical trauma of transplantation compromises the immunologic privilege, putting corneal allografts at risk for immune rejection. During the past 50 yr, rabbits, rats, and mice have been used extensively in the study of the process of immunologically mediated corneal allograft rejection. It is clear that the inflammation and neovascularization of the graft that occurs following transplantation predisposes a corneal allograft to the classic cell-mediated immune rejection response. The antigenicity of cornea cells has been studied and has been found to be significantly lower compared to other cells and tissues. Rejection of acorneal allograft is acell-mediated process directed against major histocompatibility complex antigens involving both CD4+ T helper cells and CD8+ cytotoxic cells. The prevention of corneal allograft rejection depends on the development of topically applied compounds that can prevent inflammation and vascularization and inhibit the activation of T lymphocytes. Considerable progress has been made using immunomodulators, including blocking antibodies and soluble coreceptor blocking agents such as CTLA4-Ig. Combinations of antiangiogenic agents and immunomodulators hold great promise for preventing corneal allograft rejection in patients.