Ionizing radiation is commonly used to treat cancer, with the explicit goal of eliminating an in situ tumor through reasonably well-understood direct killing mechanisms. However, the tumors that afflict patients do not evolve on plastic dishes or in immune-compromised mice. Instead, tumors develop in hosts with an intact immune system, which may serve to edit and shape the immunological phenotype of a particular lesion. Radiotherapeutic treatment of a mature tumor in an intact host results in immunologically relevant phenotypic changes in the targeted tumor cells themselves, and also has effects on the multitude of other cells that make up the tumor-associated stroma. Although many of these changes are both poorly investigated and poorly understood, recent studies have provided a new level of insight into the immunological effects of radiation, both at a local, molecular level, as well as at a systemic, whole-body level. Many of the "off-target" effects of radiation therapy might be expected to be proinflammatory, but harnessing these effects in a synergistic treatment regimen will undoubtedly require a greater knowledge and appreciation of the manner in which ionizing radiation interacts with the host.