Many studies have shown a strong association between initial graft injury and poor long-term graft outcome. Events initiated by unspecific immune-activating processes including brain death and ischemia/reperfusion injury occurring prior to transplantation reduce graft functionality and amplify the host immune response. These events may be particularly relevant for less than optimal grafts with reduced resistance to unspecific injuries. Several approaches to ameliorate immune activation of the graft by treating the donor or the graft have been studied. While various substances have been shown to have protective effects in experimental transplantation, only a few drugs have been tested clinically and have demonstrated beneficial effects. We review the results of experimental and clinical studies on donor or graft immunomodulation prior to transplantation and analyze the evidence to support clinical application of these strategies.