Radiation oncology remains an important component of care to patients treated for multiple malignancies including all liquid and solid disease types and body regions. Radiation therapy directed to tumor targets will unintentionally include normal tissue in the treatment field. Although modern technology, including image guidance and intensity modulation, permits titration of normal tissue within a therapy field, immunotherapy has the potential of potentiating normal tissue injury despite current acceptable normal tissue volumetric metrics in the therapy field and especially in patients with compromised normal tissue function at the time of therapy. In this chapter, we review current knowledge about immune expression and suppression associated with radiation therapy including changes within the immune microenvironment. We review advantages and disadvantages of immunotherapy associated with radiation therapy and identify pathways to promote tumor kill and potentially mitigate the impact of integrated therapy on normal tissue. Current protocols using immunotherapy with radiation therapy are presented. A vision for next generation studies to potentiate the impact on tumor with immunotherapy and radiation therapy is provided and includes strategies to limit and prevent acute and late injury to normal tissue. Radiation oncology and immunotherapy are both powerful tools and important to the care of the oncology patient for the next generation of clinical trials. An enhanced understanding of the integration of these tools in patient care will serve to improve patient survival and limit toxicity imposed by therapy.