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Fundamental discoveries during the 1990s revolutionized our understanding of transplantation tolerance and our ability to create it in animal models. The Immune Tolerance Network (ITN) and Reprogramming the Immune System for the Establishment of Tolerance (RISET) consortia were created to leverage these advances and work towards the goal of achieving clinical tolerance in transplantation. This article highlights their accomplishments and challenges during the past decade.In interventional trials, renal allograft tolerance has been achieved using bone marrow transplantation with nonmyeloablative protocols to induce transient hematopoietic chimerism. Drug minimization in renal transplantation was achieved with Campath-1H induction therapy and also with cellular therapy using ‘transplant acceptance inducing cells’. Successful drug withdrawal was accomplished in long-term stable pediatric liver transplant recipients. Finally, ‘registry’ trials of tolerant kidney recipients revealed a B-cell signature of tolerance, which will form the basis for future investigations of its use as a biomarker for drug minimization or withdrawal in selected patients.Although transplantation tolerance is not yet reliably achieved in a clinical setting, collaborative efforts, such as those of the ITN and RISET networks, are an effective means to synergize intellectual and financial resources to bring this goal closer to reality.