Regulatory T lymphocytes (Treg) are fundamental for immune homeostasis since they contribute to the induction of peripheral tolerance to autologous antigens and regulate effector immune responses. Treg subsets are present within both the CD4+and the CD8⁺ T cell compartments. Considering the CD8⁺ Treg, in the last decades several subpopulations, provided with different phenotypes and mechanisms of action, have been characterized. This review is an attempt of integrating in an organic scenario the different CD8⁺ Treg subpopulations. Moreover, it summarizes the findings so far achieved on the existence of CD8⁺ Treg alterations in autoimmune diseases.