Hand transplantation is the most common form of modern composite tissue allotransplantation, with 89 cases reported worldwide since 1998. The procedure is a treatment option for complex injuries that leave patients with structural, functional, and aesthetic deficits that cannot be addressed by other means. Successful application of this technology requires a multidisciplinary approach, incorporating not only skilled hand surgeons, transplant surgeons, and transplant immunologists, but also hand therapists, psychiatrists, medical specialists, anesthesiologists, and so on. Its long-term results depend on proper patient selection, a technically successful operation, postoperative rehabilitation, and an immunotherapy protocol that prevents rejection. Recent advances in transplant immunology are shifting the focus from immunosuppression to immunoregulation. Despite the enormous antigen load associated with composite tissue allografts, hand transplant has become a clinical reality, with immunosuppression comparable to that of solid-organ transplants. Our understanding of hand transplantation is still evolving, and ongoing research is needed to improve functional outcomes and to decrease the morbidity associated with long-term immunosuppression. This review discusses the current protocols for upper extremity donation, transplant receipt, surgical techniques, postoperative rehabilitation and immunosuppression, nerve regeneration, functional outcomes, ethical issues, and financial considerations.