Tumours contain multiple different cell populations, including cells derived from the bone marrow as well as cancer-associated fibroblasts and various stromal populations including the vasculature. The microenvironment of the tumour cells plays a significant role in the response of the tumour to radiation treatment. Low levels of oxygen (hypoxia) caused by the poorly organized vasculature in tumours have long been known to affect radiation response; however, other aspects of the microenvironment may also play important roles. This article reviews some of the old literature concerning tumour response to irradiation and relates this to current concepts about the role of the tumour microenvironment in tumour response to radiation treatment. Included in the discussion are the role of cancer stem cells, radiation damage to the vasculature and the potential for radiation to enhance immune activity against tumour cells. Radiation treatment can cause a significant influx of bone marrow-derived cell populations into both normal tissues and tumours. Potential roles of such cells may include enhancing vascular recovery as well as modulating immune reactivity.