The discovery of regulatory T cells (Tregs) as a crucial component of peripheral down-regulation of immunity to self and allogeneic antigens has raised legitimate hope for the development of Treg-based clinical protocols for tolerance to allografts. The present review addresses the question of whether therapeutic Tregs are ready to enter the clinical transplantation arena. In light of recent experimental observations, we will revisit some fundamentals of T cell and Treg biology that stress the need for further studies prior to applications and provide conceptual cues for novel therapeutic approaches.