Despite extensive studies on CD4(+)CD25(+) regulatory T cells (Tregs) during the past decade, the progress on their clinical translation remains stagnant. Mounting evidence suggests that naturally occurring CD8(+)CD122(+) T cells are also Tregs with the capacity to inhibit T-cell responses and suppress autoimmunity as well as alloimmunity. In fact, they are memory-like Tregs that resemble a central memory T cell (T-CM) phenotype. The mechanisms underlying their suppression are still not well understood, although they may include IL-10 production. We have recently demonstrated that programmed death-1 (PD-1) expression distinguishes between regulatory and memory CD8(+)CD122(+) T cells and that CD8(+)CD122(+) Tregs undergo faster homeostatic proliferation and are more potent in the suppression of allograft rejection than conventional CD4(+)CD25(+) Tregs. These findings may open a new line of investigation for accelerating effective Treg therapies in the clinic. In this review, we summarize the significant progress in this promising field of CD8(+)CD122(+) Treg research and discuss their phenotypes, suppressive roles in autoimmunity and alloimmunity, functional requirements, mechanisms of action and potential applications in the clinic.