Hematopoietic cell transplantation (HCT) can be an effective approach to induce allograft tolerance, replace defective blood lineages and cure hematological malignancies. Unfortunately, the toxicities associated with HCT protocols that reliably establish stable engraftment limit this approach in the clinic. Toxicities include complications resulting from cytotoxic conditioning and graft versus host disease (GvHD). One of my major scientific achievements has been the development of a novel, minimally toxic protocol that reliably establishes hematopoietic stem cell engraftment and tolerance across haploidentical MHC barriers in miniature swine without GvHD. As a confirmation of the clinical relevance of the miniature swine model, haploidentical HCT following standard myeloablation uniformly results in severe GvHD and/or hematopoietic failure. Preliminary data from my research suggest that mild HCT protocols that preserve regulatory T-cell development and function may be more successful in achieving stable donor stem cell engraftment while avoiding GvHD than those that rely on harsh conditioning and complete donor and host T-cell depletion. Another major scientific achievement has been the establishment of several leukemia and lymphoma cell lines derived from the bone marrow of older miniature swine that spontaneously developed chronic myelogenous leukemia over the past ten years as well as from experimental animals that developed post-transplantation lymphoproliferative disorder. Recently one of the myeloid leukemia cell lines demonstrated growth in vivo when injected intraosseously into MHC-matched miniature swine. The goal of these tumor studies is to develop transplantable tumor models in miniature swine to enable direct assessment of tumor immunotherapy in a clinically relevant large animal model.