Irreversible immunological rejection is the major cause of human corneal allograft failure and occurs despite the use of topical glucocorticoid immunosuppression. Systemic pharmacological interventions have not found widespread favour in corneal transplantation because of associated morbidities and inadequate demonstration of efficacy. Gene therapy offers tantalising prospects for improving corneal allograft survival, especially in those recipients at high risk of graft rejection. Donor corneas can be gene-modified ex vivo, while in storage prior to implantation, and the relative isolation of the transplanted cornea from the circulation decreases the risk of potential systemic complications. A wide variety of vectors have been found suitable for gene transfer to the cornea. The mechanisms involved in corneal graft rejection have been placed on a relatively secure footing over the past decade and in consequence a number of transgenes with promise for modulating rejection have been identified. However, relatively few studies have thus far demonstrated significant prolongation of corneal allograft survival after gene transfer to the donor cornea. In these instances, the therapeutic protein almost certainly acted at a proximal level in the afferent immune response, within the ocular environs.