The TCR-mediated recognition of self and microbial protein antigens by CD8+ T cells presented by the relatively nonvariable, class Ib MHC molecule, Qa-1 in mice and HLA-E in humans, is emerging as an important arm of the immune response. In this brief review, we will cover key examples of Qa1/HLA-E-restricted CD8+ T cells and their role in immunity against microbes and in cancer, but also as an important immunoregulatory pathway complementary to the FoxP3+CD4+ Treg. Although much remains to be learned, increased understanding of HLA-E-targeted immune responses can be potentially exploited in the development of broader and complementary immunotherapeutics against bacteria/viruses, tumors, and autoimmune diseases.