During the past 30 years, organ transplantation has developed from a highly experimental procedure into an important part of routine clinical practice. This is reflected by the fact that graft survival times, which were once considered in terms of days or weeks, are now measured in terms of years or decades, with enormous corresponding benefits for the patient. Much of this improvement is due to the development of sophisticated immunosuppressive drugs that inhibit the rejection response mediated by the immune system of the recipient. However, almost without exception, all of the grafts that are transplanted from one genetically disparate individual to another are eventually rejected. The Holy Grail in transplantation is the development of protocols that lead to transplantation tolerance and provide stable graft function without long-term drug therapy. In this article, we have discussed the need for alternatives to current immunosuppression and reviewed the results of animal models, which suggest that long-term stable tolerance is an achievable goal.