Exposure of tumourous tissue to ionizing radiation initiates a wound-healing response involving remodelling of the extracellular microenvironment. The initial reaction involves direct damage to the matrix proteins and the secretion and activation of proteolytic enzymes that lead to local destruction of the extracellular matrix. Subsequently the wounded area may undergo complete repair, may enter a prolonged period of heightened proteolysis, or may overproduce matrix proteins leading to fibrosis. The source of matrix degrading enzymatic activity may be the tumour cells and the tumour stroma. Additional complexity is provided by proteolytic activity released from tissue macrophages, mast cells and by invading inflammatory cells. The local production of growth factors, including VEGF and TGF-β play a key role in coordinating the response. It is anticipated that the application of modern proteomic technologies will reveal hitherto unrecognised levels of complexity in these processes. Hopefully this will lead to the development of new therapeutic strategies to prevent long-term health implications of radiation exposure.