Several types of T cells with immunosuppressive properties have been identified, but FOXP3(+) regulatory T (T(REG)) cells have emerged as a dominant cell type; they are critically involved in the induction and maintenance of immune tolerance. Manipulation of this cell type for the induction of transplant tolerance including renal transplant tolerance has attracted considerable attention. Studies in this area have demonstrated unexpected complexities, and attempts to translate T(REG) cells towards clinical utility have met with unanticipated difficulties. In this Review, a broad overview is provided on recent progress in the study of T(REG) cells, focusing on challenges, opportunities, and emerging approaches in exploiting T(REG) cells for the induction of transplant tolerance.