Actual treatment of brain metastasis is based on surgery and radiation. Benefit from these therapies is limited given that in most of the cases the disease relapses. Relapsed brain metastases are usually considered an end-point of the disease with no further therapeutic alternatives. The process of relapse is hypothesized to initiate from pre-existing cancer cells left behind given the inability of surgery or radiation to assess complete removal of the cancer. In spite of its clinical importance, there is no experimental data on the biology of relapse in brain metastasis. We are establishing experimental models of brain metastasis relapse after radiation therapy, study the biology of recurrence and determine the molecular regulators of this process. This approach will allow us to characterize in situ the biology of metastatic cells not eliminated by therapy until they resume a clinically relevant tumor in the brain. Our intention is to develop a bottom-up approach from the first steps of discovery towards the generation of a strong platform to validate new biomarkers that could predict the response to radiation therapy in patients, as well as novel therapeutic targets to improve the management of brain metastasis in a clinically relevant context.