Radiotherapy is successfully used to treat human cancers. However, patients locally recurring after treatment are at increased risk of developing metastases. The clinical management of this condition is a challenge, and its underlying mechanisms remain largely unknown. Since radiotherapy modifies the tumour microenvironment, we hypothesized that radiation-induced modifications of the tumour microenvironment might favour the spreading of metastatic tumour cells. Here, we report that the irradiation of naïve stroma promotes tumour metastasis through the suppression of angiogenesis, increased of tumour hypoxia and selection of aggressive tumour cell populations that retain an invasive and metastatic phenotype even when they leave their hypoxic microenvironment. Through gene expression profiling and gain and loss of function experiments, we identified the matricellular protein CYR61 as a critical mediator of tumour cell survival during hypoxia, invasion and metastasis. Inhibition of aV integrin prevented tumour cell invasion and metastasis induced by stroma irradiation and CYR61 over-expression. We found high CYR61 metagene expression to correlate with tumour hypoxia and shorter relapsefree survival in human breast cancer. These results identify CYR61 and aV-integrins as proteins that co-operate to mediate metastasis of tumours growing in irradiated stroma and as potential therapeutic targets in patients at risk for post-radiation recurrences. They also illustrate the potential impact of therapyinduced microenvironmental hypoxia in determining tumour evolution.