Regulatory T cells (Tregs) are essential to suppress harmful self-reactive T cell responses. A paper in this issue of the European Journal of Immunology analyzes the role of Tregs in preventing syngeneic graft-versus-host disease (sGVHD). In this Commentary, we address the role of antigen specificity of Tregs in this context as well as future protocols for successful allogeneic grafts transplantation. Such ideal interventions will hopefully retain a diverse repertoire of pathogen-specific T cells, while maintenance of self-, foreign- and alloantigen-specific Tregs ensures life-long graft tolerance.