Recent advances in transplant immunology are shifting the focus from immunosuppression to immunoregulation, making composite tissue allotransplantation with novel and less potent immunosuppressive regimens a possibility. Hand transplantation has been the most frequently performed human composite tissue allotransplantation, with more than 50 upper extremity-based transplants done worldwide. Further research is needed regarding immunomodulating protocols, and careful oversight and individualized screening procedures will be required as patients seeking improved quality of life through human composite tissue allotransplantation come to accept a certain level of risk in these experimental procedures. Still, composite tissue allotransplantation offers to advance transplant medicine and reconstructive surgery.