Many tumors contain a subset of neoplastic cells with stem cell–like properties that are resistant to radiation and chemotherapy. The susceptibility of these cells to antitumor effector mechanisms operative in T-cell–mediated therapies has not been examined in detail. In this report, the authors examine a panel of primary human brain tumor stem-like initiating cells expanded from high-grade gliomas to evaluate their HLA Class I antigen presentation pathways for CD8⁺ T-cell recognition, target cell susceptibility to cytolytic perforin-based killing mechanisms, and their triggering of effector cytokine production. The cover image shows mouse brain sections stained with H&E (left panel) or a human-specific antibody (anti-B23; right panel) which were injected with stem cell–like glioma-initiating cells in the presence (bottom row) or absence (top row) of antigen-specific CD8⁺ T cells. This orthotopic glioma engraftment model demonstrates the capacity of CD8⁺ T cells to eradicate the tumor-initiating activity of primary stem-like glioma cells in an antigen-specific manner. These findings suggest that brain tumor stem-like cells are targets for T-cell recognition and killing, and lay the foundation for developing immunotherapeutic approaches to eradicate this otherwise therapeutically resistant tumor cell population. For details, see the article by Brown and colleagues on page 8886 of this issue.