Successful clinical transplantation of the upper extremity has been performed in several centers. In contrast with the recipients of other immediately vascularized organ allografts, the candidate for upper extremity transplantation has been, at least during the initial effort, a healthy patient. Although it is clear that composite tissue transplantation (CTA) is a form of allografting that behaves in many ways similarly to immediately vascularized organ allografts, the issue of developing immunologic understanding of such new allografts, awaits greater clinical experience. A summary of the immunosuppressive management of the patients who received hand allografts, with a view to explore the immunologic advantages and disadvantages as well as graft toxicity of the commonly used agents, is reported. This brief overview of the immunologic considerations in CTA is presented with the purpose of summarizing the main issues that contribute to the ultimate goal of achieving tolerance. These considerations include (1) the recipients before transplantation, (2) the donors including possible pretreatment, (3) immunosuppression for induction, maintenance, and treatment of acute rejection and its diagnosis, and (4) future potential for tolerance induction.