Although transplantation has been a standard medical practice for decades, the marked morbidity from the use of immunosuppressive drugs and poor long-term graft survival remain important limitations in the field. Achieving tolerance to transplanted organs should solve both problems, but has been an elusive goal. Recent advances in the human immunological toolbox have rekindled interest in studying the small number of transplant recipients who become tolerant to their grafts over time. The development of biomarkers of transplantation tolerance holds promise to improve the care of organ allograft recipients, to provide surrogate end points of tolerance induction strategies and to advance our understanding of the human immune response to both self and foreign antigens.