Abstract: The effects of radiotherapy (RT) on the survival of cancer patients are interpreted as a consequence of the improved local control of tumors that directly decrease systemic spreading. Some of the effects of ionizing radiation are recognized as a contribution to systemic antitumor immunity, which can provide sufficient evidence for proposing a paradigm shift. Recent examples of objective responses achieved by adding radiotherapy to immunotherapy in metastatic cancer patients support this view. Preclinical data indicate that RT can convert irradiated tumor into an in situ individualized vaccine and potentiate the systemic efficacy of immunotherapy, whereas activation of the innate and adaptive immune system can enhance the local efficacy of RT. This study summarizes key evidence that support the role of radiotherapy as an immune adjuvant and some of the current challenges in translating this knowledge for clinical use.