Mounting an efficient immune response to pathogens while avoiding damage to host tissues is the central task of the immune system. Emerging evidence has highlighted the contribution of the CD8⁺ lineage of regulatory T cells to the maintenance of self-tolerance. Specific recognition of the MHC class Ib molecule Qa-1 complexed to peptides expressed by activated CD4⁺ T cells by regulatory CD8⁺ T cells triggers an inhibitory interaction that prevents autoimmune responses. Conversely, defective Qa-1-restricted CD8⁺ regulatory activity can result in development of systemic autoimmune disease. Here, we review recent research into the cellular and molecular basis of these regulatory T cells, their mechanism of suppressive activity and the potential application of these insights into new treatments for autoimmune disease and cancer.