CD8(+) T cells are regulatory T cells (Tregs) that suppress both alloimmunity and autoimmunity in many animal models. This class of regulatory cells includes the CD8(+)CD28(-), CD8(+)CD103(+), CD8(+)FoxP3(+) and CD8(+)CD122(+) subsets. The mechanisms of action of these regulatory cells are not fully understood; however, the secretion of immunosuppressive cytokines, such as interleukin (IL)-4, IL-10 and transforming growth factor beta (TGF-β) as well as the direct killing of target cells via Fas L/Fas and the perforin/granzyme B pathways have been demonstrated in various models. Further studies are necessary to fully understand the mechanisms underlying the suppressive effects of Tregs and to provide experimental support for potential clinical trials. We recently observed that CD8(+)CD122(+) Tregs more potently suppressed allograft rejection compared to their CD4(+)CD25(+) counterparts, supporting the hypothesis that CD8(+) Tregs may represent a new and promising Treg family that can be targeted to prevent allograft rejection in the clinic. In this review, we summarize the progress in the field during the past 7-10 years and discuss CD8(+) Treg phenotypes, mechanisms of action, and their potential clinical applications; particularly in composite tissue transplants in burn and trauma patients.