The search for tolerance therapies that would thwart the alloimmune response following organ transplantation while preserving a patient's protective immune response has been a formidable goal for clinical immunologists. Over the past few decades, a more detailed understanding of the molecular events associated with T-cell recognition and activation has demonstrated the feasibility of various tolerance approaches, such as costimulation blockade, in numerous animal models of both autoimmunity and transplantation. Yet, only a few promising new therapies have reached the early stages of human clinical development. In contrast, the use of T-cell depleting induction therapy has become widespread, and new trials have been designed with immunosuppressive drug withdrawal in mind. Furthermore, nonmyeloablative mixed chimeric approaches have allowed complete immunosuppressive withdrawal in some limited cases. In the course of these investigations, however, what has become increasingly clear is that the distinctions between immunosuppression and tolerance have been blurred as the success and durability of the therapies rely as much on the state of the organ and organism as they do the mechanism of action of the drug. In this review, we provide a summary of the progress and lessons in promoting clinical transplant tolerance and an overview of promising agents.