Since the start of the clinical vascularized composite allotransplantation (VCA) era over a decade ago this field has witnessed significant developments in both basic and translational research. Transplant tolerance, defined as rejection-free acceptance of transplanted organs or tissues without long-term immunosuppression, holds the potential to revolutionize the field of VCA by removing the need for life-long immunosuppression. While tolerance of organ and vascularized composite transplants may be induced in small animal models by a variety of protocols, only mixed-chimerism-based protocols have successfully bridged the gap to preclinical study and to clinical trial in solid organ transplantation to date. In this paper we review the mixed-chimerism approach to tolerance induction, with specific reference to the field of VCA transplantation, and provide an overview of some novel cellular therapies as potential adjuvants to mixed chimerism in the development of tolerance induction protocols for clinical vascularized composite allotransplantation.