Over the last three decades considerable evidence has accumulated that CD8⁺ T cells regulate peripheral immune responses, in part, by specifically controlling the outgrowth of antigen-triggered CD4⁺ T cells. This regulatory function of CD8⁺ T cells has been shown, in vivo, to control the emergence of autoreactive CD4⁺ T cells as well as CD4⁺ T cells reactive to conventional antigens, including alloantigens. In this review, we summarize the evidence that this immune suppression mediated by CD8⁺ T cells is dependent, in part, on specific cognate interactions between MHC class I–restricted regulatory CD8⁺ cells and antigen-activated CD4⁺ T cells. Moreover, we review the evidence that regulatory CD8⁺ T cells recognize antigen-activated CD4⁺ T cells in a TCR specific manner restricted by the MHC class Ib molecule, Qa-1. The Qa-1 molecule may be uniquely qualified to serve this MHC restrictive function because, unlike conventional MHC molecules, it is preferentially and transiently expressed on activated and not resting CD4⁺ T cells. This may assure that only recently antigen-activated CD4⁺ T cells expressing Qa-1/TCR peptide complexes will induce regulatory CD8⁺ T cells and subsequently become susceptible to regulation. Because Qa-1 also binds to self Qdm peptides that trigger NK (CD94/ NKG2) receptors on CD8⁺ T cells, the machinery for homeostatic regulation of regulatory CD8⁺ T cells can be envisioned. Finally, we propose a model by which these TCR specific, Qa-1-restricted regulatory CD8⁺ T cells selectively downregulate antigen-activated T cells expressing TCRs of certain affinities. Ultimately these regulatory CD8⁺ T cells control the peripheral TCR repertoire during the course of immune responses to both self and foreign antigens.