A human memory T-cell subset with stem cell-like properties has been identified, characterized by enhanced self-renewal and multipotency to generate central memory, effector memory, and effector T cells. These cells, specific for multiple viral and self-tumor antigens, reside within a CD45RO⁻, CCR7⁺, CD45RA⁺, CD62L⁺, CD27⁺, CD28⁺, and IL-7Rα⁺ T-cell compartment typically associated with naive T cells. Despite their naive-like phenotype, they express increased levels of CD95, IL-2Rβ, CXCR3, and LFA-1, and exhibit functional attributes of memory cells. Compared to conventional memory populations, these lymphocytes show increased proliferative capacity, efficient reconstitution of immunodeficient hosts, and superior anti-tumor responses in humanized mouse models. The identification of this human stem cell-like memory T-cell population has direct relevance to vaccine and T-cell therapy design. Long-lived self-renewing memory lymphocytes are a hallmark of the adaptive immune system. Memory T cells are heterogeneous and traditionally divided into central memory (T_CM) and effector memory (T_EM) subsets. However, a novel population of memory T cells with enhanced stem cell-like qualities has been identified, designated as memory stem cells (T_SCM). These cells exhibit a CD44⁻ CD62L⁺ phenotype like naive T cells but also express stem cell antigen-1 (Sca-1) and high levels of Bcl-2, IL-2Rβ, and CXCR3. T_SCM cells were identified in human blood and represent about 2–3% of all circulating CD8⁺ and CD4⁺ T lymphocytes. They display characteristics of both naive and memory T cells, including high levels of CD95 and IL-2Rβ, and have the ability to rapidly acquire effector functions upon antigen rechallenge. T_SCM cells also show enhanced self-renewal and multipotency, generating all memory T-cell subsets in vitro. They have increased proliferative capacity, survival, and anti-tumor activity compared to conventional memory T cells. T_SCM cells were shown to be more effective than conventional memory T cells in a humanized mouse model, demonstrating enhanced anti-tumor activity and therapeutic efficacy. The identification of T_SCM cells provides new insights into the biology of memory T cells and has implications for the design of T-cell-based vaccines and therapies. These findings suggest that T_SCM cells represent a unique and important subset of memory T cells with potential applications in cancer immunotherapy and the treatment of infectious diseases.A human memory T-cell subset with stem cell-like properties has been identified, characterized by enhanced self-renewal and multipotency to generate central memory, effector memory, and effector T cells. These cells, specific for multiple viral and self-tumor antigens, reside within a CD45RO⁻, CCR7⁺, CD45RA⁺, CD62L⁺, CD27⁺, CD28⁺, and IL-7Rα⁺ T-cell compartment typically associated with naive T cells. Despite their naive-like phenotype, they express increased levels of CD95, IL-2Rβ, CXCR3, and LFA-1, and exhibit functional attributes of memory cells. Compared to conventional memory populations, these lymphocytes show increased proliferative capacity, efficient reconstitution of immunodeficient hosts, and superior anti-tumor responses in humanized mouse models. The identification of this human stem cell-like memory T-cell population has direct relevance to vaccine and T-cell therapy design. Long-lived self-renewing memory lymphocytes are a hallmark of the adaptive immune system. Memory T cells are heterogeneous and traditionally divided into central memory (T_CM) and effector memory (T_EM) subsets. However, a novel population of memory T cells with enhanced stem cell-like qualities has been identified, designated as memory stem cells (T_SCM). These cells exhibit a CD44⁻ CD62L⁺ phenotype like naive T cells but also express stem cell antigen-1 (Sca-1) and high levels of Bcl-2, IL-2Rβ, and CXCR3. T_SCM cells were identified in human blood and represent about 2–3% of all circulating CD8⁺ and CD4⁺ T lymphocytes. They display characteristics of both naive and memory T cells, including high levels of CD95 and IL-2Rβ, and have the ability to rapidly acquire effector functions upon antigen rechallenge. T_SCM cells also show enhanced self-renewal and multipotency, generating all memory T-cell subsets in vitro. They have increased proliferative capacity, survival, and anti-tumor activity compared to conventional memory T cells. T_SCM cells were shown to be more effective than conventional memory T cells in a humanized mouse model, demonstrating enhanced anti-tumor activity and therapeutic efficacy. The identification of T_SCM cells provides new insights into the biology of memory T cells and has implications for the design of T-cell-based vaccines and therapies. These findings suggest that T_SCM cells represent a unique and important subset of memory T cells with potential applications in cancer immunotherapy and the treatment of infectious diseases.