Reconstructive transplantation has emerged as clinical reality over the past decade. Utilizing standard immunosuppressive drugs has proven feasible in face and hand transplantation to achieve long-term graft acceptance. As vascularized composite tissue allotransplantation is not a life-saving procedure compared to solid organ transplantation alternative protocols with less long-term side effects are even more desirable. Allograft tolerance is the holy grail of many cell-based concepts and recent data in the field is most promising. Immunomodulation with mesenchymal stem cells from bone marrow and adipose tissue has shown high potential in this respect. This article is aiming at giving an overview on the experimental studies available, the scientific background and clinical applications. Furthermore we address essential questions prior to the use of mesenchymal stem cells in reconstructive allotransplantation.