Immune regulation is critically important in health and disease. These immune effects have direct relevance in the setting of allogeneic hematopoietic cell transplantation (HCT), principally for the control of aberrant immune reactions, such as graft-versus-host disease (GVHD). Murine models have been critically important to evaluate the potential of two of the most potent immune regulatory cells CD4+CD25+FoxP+ regulatory T cells (Treg) and invariant natural killer T cells (iNKT cells). These cells have been shown to be remarkably effective in murine models to control GVHD and allow for the maintenance of graft-versus-tumor (GVT) effects. Interestingly, there are critical interactions between these different cell populations. Future studies are aimed at exploring the biology of these important regulatory cells and to translate these concepts to the clinic that holds promise for controlling some of the major challenges of allogeneic HCT.