The combination of radiation therapy and immunotherapy holds enticing promise as a strategy for cancer treatment. Preclinical studies have shown that radiation may act synergistically with immunotherapy to enhance or broaden antitumor immune responses, in part, because of radiation-induced phenotypic alterations of tumor cells that render them more susceptible to immune-mediated killing. Clinical trials utilizing the combination of therapeutic vaccines with radiation have supported many of these findings, and other clinical trials are both ongoing and planned. This review examines the evidence that radiation induces immunological death, the mechanisms by which radiation therapy can induce or augment antitumor immune responses, and translational studies demonstrating that immunotherapy can be effectively combined with radiation therapy. Finally, recent and current clinical trials combining radiation therapy with immunotherapy are reviewed.