Cytotoxic CD8+ T cells (CTLs) are an essential component of the immune defence against viruses and tumours, because of their ability to directly kill diseased host cells. However, inappropriate activation of CTLs can result in autoimmunity, and as such, in the absence of disease, CTLs must be actively maintained in a quiescent state, whereby a threshold for activation must be overcome. Recent studies have identified that the Glucocorticoid Induced Leucine Zipper (GILZ) restrains activation of B cells and CD4+ T lymphocytes, and on this basis we hypothesised that GILZ also regulates CTL activation. Indeed we find that Gilz has a highly regulated transcriptional profile in CTLs, being strongly expressed in quiescent CTLs, whist powerfully and rapidly repressed with activation. Further, consistent with GILZ being a negative regulator of CTL activation, only activation signals strong enough to induce T cell immunity result in Gilz repression, while enforced GILZ expression blocks T cells activation under these conditions. Mechanistically, GILZ appears to bind directly to the promoters of genes encoding transcription factors, including Irf4 and Batf, that drive CTL immune activation. This suppressive effect mediated by GILZ is likely crucial, as antigen specific CTLs that lacked Gilz generated a hyperproliferative response to Influenza A Virus, supporting our hypothesis that GILZ negatively regulates CTL activation. Taken together, our data suggest that GILZ is a novel regulator and safeguard of CTL activation and differentiation, which may be targeted to enhance current immune therapy strategies.