Radiotherapy is generally used to treat a localised target that includes cancer. Increasingly, evidence indicates that radiotherapy recruits biological effectors outside the treatment field and has systemic effects. We discuss the implications of such effects and the role of the immune system in standard cytotoxic treatments. Because the effects of chemotherapy and radiotherapy are sensed by the immune system, their combination with immunotherapy presents a new therapeutic opportunity. Radiotherapy directly interferes with the primary tumour and possibly reverses some immunosuppressive barriers within the tumour microenvironment—ideally, recovering the role of the primary tumour as an immunogenic hub. Local radiation also triggers systemic effects that can be used in combination with immunotherapy to induce responses outside the radiation field.