Since the rebirth of regulatory (formerly known as suppressor) T cells in the early 1990s, research in the field of immune-regulation by various T cell populations has quickly gained momentum. While T cells expressing the transcription factor Foxp3 are currently in the spotlight, several other T cell populations endowed with potent immunomodulatory capacities have been identified in both the CD8⁺ and CD4⁺ compartment. The fundamental difference between CD4⁺ and CD8⁺ T cells in terms of antigen recognition suggests non-redundant, and perhaps complementary, functions of regulatory CD4⁺ and CD8⁺ T cells in immunoregulation. This emphasizes the importance and necessity of continuous research on both subpopulations of regulatory T cells (Tregs) so as to decipher their complex physiological relevance and possible synergy. Two distinct CD8-expressing Treg populations can be distinguished based on expression of the co-stimulatory receptor CD28. Here, we review the literature on these (at least in part) thymus-derived CD28^low and peripherally induced CD28⁻CD8⁺ Tregs.