Composite tissue allografts are made of histogenetically different tissues and although skin seems to be the most antigenic of them, it is unknown whether the dominant immune response is really directed against the skin or we have insufficient information on the involvement of the other components of these allografts. The first clinical signs of acute rejection manifest on the skin and microscopically the earliest lesions consist in a dermal perivascular lymphocytic infiltrate, predominantly made of CD3+/CD4+ T cells. On the basis of the histological changes, a specific score (Banff score 2007) has been established to assess the severity of rejection. Despite the high incidence of acute rejection episodes, they can be completely reversed when promptly diagnosed and treated. C4d deposits in the skin and circulating donor-specific antibodies are rarely detected, suggesting that humoral rejection does not play a significant role in composite tissue allotransplantation. Chronic rejection features are still unknown. The majority of recipients have been maintained on an immunosuppressive regimen consisting of tacrolimus, steroids, and mycophenolate mofetil. The complications in composite tissue allotransplantation are similar to those usually reported after solid organ transplantation and have prompted different strategies to minimize the maintenance immunosuppression or to induce donor-specific tolerance. Furthermore, to what extent the immunosuppression can be tapered is unknown, as well as the influence of donor bone-marrow infusion in tolerance and chronic rejection. The increasing number of patients and the longer follow-up hopefully will allow answering these questions.