The concept of composite tissue allotransplantation (CTA) for restoration of congenital or acquired deformities is not new and the recent success of clinical composite tissue allotransplantation (CTA) attests to the fact that composite tissue allografts have tremendous potential in these life–enhancing reconstructions. A hand transplant, unlike a solid organ transplant, involves multiple tissues (skin, muscle, tendon, bone, cartilage, fat, nerves and blood vessels) and can be considered the ‘gold standard’ in CTA. In this regard, no other organ or tissue transplant matches the hand transplant in its immunogenicity as well as complexity. Development of assays that allow us to monitor the current state of an immune response (rejection/tolerance) is of great interest and requires an in–depth understanding of the complex and rare phenomenon of tolerance.