Chemotherapy and radiotherapy have been extensively used to eradicate cancer based on their direct cytocidal effects on rapidly proliferating tumor cells. Accumulating evidence indicates that these therapies also dramatically affect resident and recruited immune cells that actively support tumor growth. We now appreciate that mobilization of effector CD8⁺ T cells enhances the efficacy of chemotherapy and radiotherapy; remarkable clinical advances have been achieved by blocking regulatory programs limiting cytotoxic CD8⁺ T cell activity. This review discusses immune-mediated mechanisms underlying the efficacy of chemotherapy and radiotherapy, and provides a perspective on how understanding tissue-based immune mechanisms can be used to guide therapeutic approaches combining immune and cytotoxic therapies to improve outcomes for a larger subset of patients than is currently achievable.