Major advances in the knowledge of cancer biology and its interactions with tumor immune environment led to the emergence, in the last five years of new immunotherapy-based treatment strategies in cancer patients. At the same time, improvement in radiation technique and progress in radiobiology allowed in the last decade to expand the applications of radiotherapy in a growing number of settings. At present, there are strong theoretical basis to propose immune-enhanced radiation therapy that may represent in the future a new paradigm of treatment, combining the intrinsic power of radiotherapy to elicit a specific, systemic, tumor-directed immune response with modern highly conformal and precise dose delivery, in order to maximize response at the major site of disease and obtain durable disease control. The aim of this review is to describe the principal mechanisms of immune modulation of response to radiation and investigational strategies to harness the potential of radiation-inducible immune response: radiation therapy is expected to be not just a local treatment but the cornerstone of a multimodal strategy that might achieve long-lasting tumor remission at the primary site and systemic efficacy metastatic lesions. (C) 2017 Elsevier B.V. All rights reserved.