In the past 40 years, transplantation has moved from an experimental form of therapy used almost exclusively for renal failure to an accepted treatment for end-stage kidney disease, heart disease, liver disease, lung disease, and diabetes mellitus. Tissue transplantation for conditions from thermal injury to Parkinson disease is being investigated. The primary barrier in transplantation medicine is the immunologic reaction of the recipient to donor organs and tissues. Currently available drugs permit excellent short-term graft survival but have not led to reliable long-term survival. Recent advances in the understanding of this immune response have suggested new approaches to induction of immunologic tolerance and reduction of late graft losses. Because of the excellent short-term success of current agents, integration of these new approaches into clinical trials is challenging and raises important questions about the design of such trials.