This chapter provides an overview of the use of the most current immunosuppressive medications in composite tissue transplantation, and the immunological issues regarding the long-term survival of tissue allografts. Because the clinical application of composite tissue transplantation has been either anecdotal (laryngeal, bone, tendon) or recent (hand transplantation), the risk of late allograft loss is for the most part extrapolated from the organ transplantation literature. Peripheral nerve transplantation is unique because the nerve allograft provides only a temporary scaffold to guide host nerve regeneration; immunosuppressive medication is required for only a couple of years, and long-term allograft survival is not relevant. On the basis of the experience in organ transplantation, chronic rejection remains a significant and unsolved problem despite the use of the most potent immunosuppressive drugs. Since composite tissue transplantation improves quality of life but is nonvital, allograft longevity will continue to be a critical issue in the justification of hand and face transplantation.