Significance Memory CD8 T lymphocytes are a long-lived population of immune cells that provide formidable protection against infections and malignancy and are thus often central to vaccine and cancer immunotherapy efficacy. Here we refine the identity, developmental relationships, and functional roles of memory CD8 T cells in mice through delineation of a discrete population that confers robust protection against reinfection and exhibits an unexpected molecular program bearing typically divergent characteristics of short-lived effector cells and long-lived memory T cells. Mass cytometry and single-cell RNA-sequencing analyses revealed an analogous population of cells in humans. These findings hold broad implications for both informing immunotherapy treatments and predicting their efficacy.