Local administration of ionizing radiation to tumors can promote anticancer immune responses that lead to the abscopal regression of distant metastases, especially in patients receiving systemic immune-checkpoint inhibitors. Growing preclinical evidence indicates that high-dose irradiation administered locally to destroy malignant lesions, can promote the release of danger-associated molecular patterns that lead to the recruitment of immune cells, thus inducing a systemic response against tumor antigens that protects against local disease relapse and also mediates distant antineoplastic effects. An accumulating body of preclinical evidence supports also the implementation of low-dose irradiation to induce tumor immune reprogramming. Here, we provide the rationale for a clinical research agenda to refine future clinical practice based on innovative combinations of radiation-immunotherapy.