Allograft rejection is the most common reason for corneal transplant failure, despite the immunologic privilege of both the graft and the anterior chamber. To prevent corneal allograft rejection, various immunomodulatory strategies have been used in experimental corneal transplantation. These include (1) anti-T-cell receptor and T-cell depletion therapy; (2) manipulation of costimulatory molecule function, including both down-regulation of positive stimulatory molecules and/or up-regulation of inhibitory molecules and overproduction of tumor necrosis factor-related, apoptosis-induced ligand; (3) modulation of cytokine production by reducing proinflammatory cytokines (tumor necrosis factor alpha, interleukin [IL]-12, and IL-1) and/or increasing immunoregulatory cytokines (IL-10 and IL-4); (4) macrophage depletion; and (5) overexpression of the immunomodulatory molecule indoleamine 2,3-dioxygenase. Although these approaches appear promising in animal corneal transplantation models, there has been very little translation of these immunomodulatory approaches in human corneal transplantation.