Molecular biologic studies have elucidated the roles of specific and innate immune responses in the pathogenesis of HSV keratitis. Recent evidence suggests that interference with innate immune mechanisms may reduce the severity of HSV keratitis and its complications. The agents targeting innate immune responses are particularly amenable to translational therapy for patients at risk of complications of HSV keratitis and poor corneal transplant outcomes. Histopathologic evidence of neovascularization or inflammation in tissue removed at the time of corneal transplantation predicts patients who are at risk for allograft rejection or failure. Such patients are prime candidates for close monitoring and intensive therapy. Newer imaging techniques, such as clinical confocal biomicroscopy, might be useful in identifying neovascularization and inflammation that place patients at high risk for poor allograft outcomes prior to corneal transplantation.