Long-term survival of transplanted organs currently requires chronic immunosuppressive treatment of recipients. While the efficacy of these therapies is satisfactory, their toxicity to host tissues and non-specific inhibition of the immune response are disadvantageous. The ideal in transplantation is a situation of donor-specific unresponsiveness, but agents capable of effecting specific tolerance to transplanted tissues have been elusive. Accumulating evidence suggests that immunoregulatory CD4⁺CD25⁺T cells are essential in regulating the immune response to self and foreign antigen. As these cells are capable of suppressing the alloresponse, they represent a potentially invaluable tool for prolonging survival of allografts. In this report, we summarize studies characterizing regulatory T cells and addressing their ability to extend allograft survival. While the capacity of this population to promote allograft tolerance has been demonstrated, many questions remain to be answered before their potential for clinical applicability can be fully defined. Despite this, it is clear from initial studies that regulatory T cells represent an exciting avenue for further investigation in the quest to induce donor-specific unresponsiveness.