Research into the suppressive activity of CD4(+)FoxP3(+) T regulatory cells (Treg) has defined a sublineage of CD4(+) cells that contribute to self-tolerance and resistance to autoimmune disease. Much less attention has been given to the potential contribution of regulatory sublineages of CD8(+) cells. Analysis of a small fraction of CD8(+) cells that target autoreactive CD4(+) cells through recognition of the MHC class Ib molecule Qa-1 in mouse and HLA-E in human has revitalized interest in CD8(+) Treg. Here we summarize recent progress and future directions of research into the role of this CD8(+) sublineage in resistance to autoimmune disease.