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Brain tumors are composed of primary tumors of the central nervous system, such us glioblastoma (GBM), and secondary metastatic tumors, such as melanoma, non-Hodgkin lymphoma as well as lung and breast cancers. Brain tumors are highly deadly, and unfortunately not many improvements have been achieved to improve the survival of patients with brain tumors. Chemoradiation resistance is one of the most clinically relevant challenges faced in patients with brain tumors. The perivascular niche is one of the most relevant microenvironment hubs in brain tumors. The understanding of the cellular crosstalk established within the brain tumor perivascular niche might provide us with key discoveries of new brain tumor vulnerabilities.Radio and chemoresistance in GBM and brain metastases is attributed to cancer stem cells (CSCs), which intrinsically modulate several pathways that make them resistant to therapy. Growing evidence, however, highlights the perivascular space as a niche for CSC survival, resistance to therapy, progression and dissemination. Here, I review the latest discoveries on the components and features of brain tumor vascular niches and the possible therapeutic strategies aimed at targeting its vulnerabilities, thus preventing GBM and metastasis chemoradiation resistance and recurrence.Recent discoveries suggest that targeting the brain perivascular niche has the potential of sensitizing brain tumors to therapies and reducing the occurrence of metastases.