CD8 T cells are the cytotoxic effectors of the adaptive immune response, clearing virally infected and cancerous cells within the host. CD8 T cells acquire their cytotoxic function by differentiating into cytotoxic T lymphocytes (CTLs). Once the CTLs have cleared the antigen, the majority of responding cells will die during contraction; however, a small population of the antigen-specific responders will remain, differentiating into long-lived memory cells that provide potent protection to the host upon re-encounter with the antigen. These differentiation programs often become disturbed in cases of chronic infection and cancer. Instead, CD8 T cells are subverted into the so-called exhausted state, in which cells become functionally inert. As such, the ability to program the differentiation of CD8 T cells into a particular fate is an important therapeutic strategy. We have identified a global post-transcriptional mechanism that determines the fate of differentiating CD8 T cells. Specifically, we have found that the let-7 family of miRNAs is abundantly expressed in naïve CD8 T cells, and that this expression is downregulated upon T cell receptor signaling. The expression of let-7 in naïve CD8 T cells was demonstrated to be necessary and sufficient to maintain the quiescent state of naïve cells. Accordingly, the down-regulation of let-7 is necessary for the differentiation of naïve CD8 T cells into cytotoxic T lymphocytes in vitro. However, let-7 expression had paradoxical effects on CD8 T cell function in vitro and in vivo. Specifically, loss of let-7 expression drives the differentiation of terminal effector CD8 T cells, which in immunosuppressive environments in vivo, are diverted into the exhausted state. Accordingly, maintaining let-7 expression restrained terminal effector differentiation, and programmed CD8 T cells to differentiate into highly protective memory cells. These findings may have important implications for the improvement of current immunotherapies targeting CD8 T cell fate.