Establishment of mixed hematopoietic chimerism carries with it the induction of transplantation tolerance to any other tissue or organ from the same donor. This strategy has been studied extensively for induction of tolerance in mice. During the past decade, we have extended the same strategy, with modifications, to cynomolgus monkeys and most recently to renal transplant patients. In this report we review the evolution of these studies from preclinical applications to our current clinical experience with two therapeutic protocols sponsored by the Immune Tolerance Network. The first of these studies is for patients with myeloma and end-stage renal disease with an HLA-matched sibling donor; the second for patients with end-stage renal disease and HLA-mismatched donors. Although it is still early in the course of these studies, the results to date are very encouraging.