Transplantation is the treatment of choice for many if not most causes of end-stage organ failure. Over 20,000 organ transplant procedures were performed in the USA in 2009 to treat patients with failed or failing kidneys, livers, hearts, lungs, and intestines, and there remain 85,000 individuals waiting on the transplant list. Currently, in the USA, there are over 170,000 individuals living with a transplanted organ. Virtually, all of these individuals receive maintenance immunosuppression in an attempt to maximize the function and survival of the transplanted organ. However, it is clear that the long-term use of immunosuppressive agents is associated with an extensive list of undesirable side effects that have the potential to limit the survival of the patient and transplanted organ as well as to compromise quality of life. Although the ability to induce reproducibly a state of robust, stable tolerance would address this problem, tolerance remains an infrequent event in clinical transplantation that is largely a consequence of chance. Factors limiting the broader investigation of clinical transplantation tolerance include the lack of therapeutic regimens known to favor tolerance in humans, the lack of validated assays or biomarkers predictive of tolerance, and concerns about the safety and ethics of complete withdrawal of immunosuppression given the very good results achievable with current immunosuppression. Despite these barriers, a number of investigators have continued to conduct well-designed and carefully supervised studies with the long-term goal of making clinical transplantation tolerance more feasible. The aim of this review is to summarize the status of these studies.