Organ transplantation is now firmly established as the therapy of choice for end-stage organ failure. Specific immunological tolerance of transplant recipients towards their foreign organ or tissue grafts is a goal that has been sought by transplant biologists for almost 50 years following the original description of the phenomenon in experimental animals by Medawar and colleagues. Since that time, a wealth of experimental data has accumulated relating to strategies for extending allograft survival and function. Recent studies have shed new light on the molecular and cellular basis of transplant rejection and have better defined the mechanisms of allograft tolerance with particular emphasis on a role for regulatory T cells. Still, the question remains of how near we are to the day when long-term tolerance of engrafted organs or tissues will be a clinical reality. Recently, clinical trials to explore pilot tolerance protocols in humans have been initiated under the auspices of the Immune Tolerance Network (www.immunetolerance.org). In this review we will highlight the promise and challenges of making transplantation tolerance a clinical reality.