It is now possible to induce donor‐specific transplantation tolerance in adult rodents using non‐depleting monoclonal antibodies against T cell co‐receptor and co‐stimulation molecules or by immunisation with tolerogenic antigen‐presenting cells. It is a common finding of all these models of peripheral tolerance, as well as of various mouse models of autoimmune disease, that regulatory CD4⁺ T cells are the principal mediators. There are currently no specific markers for regulatory T cells, but in some autoimmune models their activity has been associated with the expression of activation markers such as CD25 and CTLA4, or anti‐inflammatory cytokines such as IL‐10 and TGF‐β. CD4⁺CD25⁺ T cells from both naïve and tolerised donors are able to transfer tolerance to grafts in lymphopenic recipients, and this may be directly applicable to bone‐marrow transplantation. The challenge is now to understand the biological principles that allow such immune re‐programming so that they can be safely applied to clinical organ grafting.