Loss of an isolated upper limb is an emotionally and physically devastating event that results in significant impairment. Patients who lose both upper extremities experience profound disability that affects nearly every aspect of their lives. While prosthetics and surgery can eventually provide the single limb amputee with a suitable assisting hand, limited utility, minimal haptic feedback, weight, and discomfort are persistent problems with these techniques that contribute to high rates of prosthetic rejection. Moreover, despite ongoing advances in prosthetic technology, bilateral amputees continue to experience high levels of dependency, disability, and distress. Hand and upper extremity transplantation holds several advantages over prosthetic rehabilitation. The missing limb is replaced with one of similar skin color and size. Sensibility, voluntary motor control, and proprioception are restored to a greater degree, and afford better dexterity and function than prosthetics. The main shortcomings of transplantation include the hazards of immunosuppression, the complications of rejection and its treatment, and high cost. Hand and upper limb transplantation represents the most commonly performed surgery in the growing field of Vascularized Composite Allotransplantation (VCA). As upper limb transplantation and VCA have become more widespread, several important challenges and controversies have emerged. These include: refining indications for transplantation, optimizing immunosuppression, establishing reliable criteria for monitoring, diagnosing, and treating rejection, and standardizing outcome measures. This article will summarize the historical background of hand transplantation and review the current literature and concepts surrounding it.