mTOR regulates memory CD8 T cell differentiation. This study shows that mTOR, a mammalian target of rapamycin, is a major regulator of memory CD8 T cell differentiation. Surprisingly, the mTOR inhibitor rapamycin, an immunosuppressive drug, had immunostimulatory effects on memory CD8 T cell generation. Treatment of mice with rapamycin after acute lymphocytic choriomeningitis virus (LCMV) infection enhanced both the quantity and quality of virus-specific CD8 T cells. Similar effects were observed after immunization with a non-replicating VLP-based vaccine. Rapamycin also enhanced memory T cell responses in non-human primates following vaccination with MVA. Rapamycin was effective during both the expansion and contraction phases of the T cell response. During the expansion phase, it increased the number of memory precursors, and during the contraction phase, it accelerated memory T cell differentiation. Experiments using RNAi to inhibit mTOR, raptor, or FKBP12 expression in antigen-specific CD8 T cells showed that mTOR acts intrinsically through the mTORC1 pathway to regulate memory T cell differentiation. These findings identify a molecular pathway regulating memory formation and provide a strategy for improving the functional qualities of vaccine or infection-induced memory T cells. Rapamycin is a commonly used immunosuppressive drug that inhibits the intracellular kinase mTOR. Recent studies have shown that rapamycin has various effects on the immune system, including inhibiting type I interferon production by plasmacytoid dendritic cells, modulating T cell trafficking, and regulating Foxp3 expression in regulatory T cells. However, the role of the mTOR pathway in regulating CD8 T cell responses is not known. The study found that rapamycin enhanced the LCMV-specific CD8 T cell response, increased the number of antigen-specific CD8 T cells in both lymphoid and non-lymphoid tissues, and decreased the contraction of the T cell response. Rapamycin treatment also enhanced the survival of antigen-specific CD8 T cells. The phenotype of memory CD8 T cells in the two groups of mice was analyzed, and memory CD8 T cells generated in the presence of rapamycin expressed higher levels of CD127, CD62L, and Bcl-2, and had a higher frequency of KLRG-1 low cells compared to control mice. These data suggest that inhibition of the mTOR pathway using rapamycin not only increased the magnitude of the virus-specific CD8 T cell response but also improved the functional qualities of the memory CD8 T cells. Rapamycin treatment during the effector to memory transition phase enhanced the memory differentiation program, resulting in a significantly higher number of virus-specific CD8 T cells with the phenotype characteristic of highly functional memory cells. The study also showed that rapamycin enhances both the magnitude and quality of the CD8mTOR regulates memory CD8 T cell differentiation. This study shows that mTOR, a mammalian target of rapamycin, is a major regulator of memory CD8 T cell differentiation. Surprisingly, the mTOR inhibitor rapamycin, an immunosuppressive drug, had immunostimulatory effects on memory CD8 T cell generation. Treatment of mice with rapamycin after acute lymphocytic choriomeningitis virus (LCMV) infection enhanced both the quantity and quality of virus-specific CD8 T cells. Similar effects were observed after immunization with a non-replicating VLP-based vaccine. Rapamycin also enhanced memory T cell responses in non-human primates following vaccination with MVA. Rapamycin was effective during both the expansion and contraction phases of the T cell response. During the expansion phase, it increased the number of memory precursors, and during the contraction phase, it accelerated memory T cell differentiation. Experiments using RNAi to inhibit mTOR, raptor, or FKBP12 expression in antigen-specific CD8 T cells showed that mTOR acts intrinsically through the mTORC1 pathway to regulate memory T cell differentiation. These findings identify a molecular pathway regulating memory formation and provide a strategy for improving the functional qualities of vaccine or infection-induced memory T cells. Rapamycin is a commonly used immunosuppressive drug that inhibits the intracellular kinase mTOR. Recent studies have shown that rapamycin has various effects on the immune system, including inhibiting type I interferon production by plasmacytoid dendritic cells, modulating T cell trafficking, and regulating Foxp3 expression in regulatory T cells. However, the role of the mTOR pathway in regulating CD8 T cell responses is not known. The study found that rapamycin enhanced the LCMV-specific CD8 T cell response, increased the number of antigen-specific CD8 T cells in both lymphoid and non-lymphoid tissues, and decreased the contraction of the T cell response. Rapamycin treatment also enhanced the survival of antigen-specific CD8 T cells. The phenotype of memory CD8 T cells in the two groups of mice was analyzed, and memory CD8 T cells generated in the presence of rapamycin expressed higher levels of CD127, CD62L, and Bcl-2, and had a higher frequency of KLRG-1 low cells compared to control mice. These data suggest that inhibition of the mTOR pathway using rapamycin not only increased the magnitude of the virus-specific CD8 T cell response but also improved the functional qualities of the memory CD8 T cells. Rapamycin treatment during the effector to memory transition phase enhanced the memory differentiation program, resulting in a significantly higher number of virus-specific CD8 T cells with the phenotype characteristic of highly functional memory cells. The study also showed that rapamycin enhances both the magnitude and quality of the CD8