T memory stem (T_SCM) cells are a rare subset of memory lymphocytes endowed with the stem cell–like ability to self-renew and the multipotent capacity to reconstitute the entire spectrum of memory and effector T cell subsets. Cumulative evidence in mice, nonhuman primates and humans indicates that T_SCM cells are minimally differentiated cells at the apex of the hierarchical system of memory T lymphocytes. Here we describe emerging findings demonstrating that T_SCM cells, owing to their extreme longevity and robust potential for immune reconstitution, are central players in many physiological and pathological human processes. We also discuss how T_SCM cell stemness could be leveraged therapeutically to enhance the efficacy of vaccines and adoptive T cell therapies for cancer and infectious diseases or, conversely, how it could be disrupted to treat T_SCM cell driven and sustained diseases, such as autoimmunity, adult T cell leukemia and HIV-1.