The brain tumor microenvironment (TME) is a critical regulator of cancer progression in primary and metastatic brain malignancies. The unique properties of the brain, including its immune privilege, distinct extracellular matrix (ECM), and the blood-brain barrier (BBB), necessitate a specific framework for designing targeted interventions. This review highlights the distinct features of the brain TME, such as the presence of brain-resident cell types, the BBB, and an immunosuppressive environment. Recent advances in therapeutically targeting the brain TME are discussed, emphasizing the importance of understanding the complex and interconnected microenvironmental landscape of brain malignancies to expand therapeutic strategies. The review focuses on gliomas, brain metastases, and medulloblastoma, highlighting the context-dependent roles of various immune cell types, the BBB, angiogenesis, and the ECM. It also explores the potential of targeting astrocytes, neurons, and the lymphatic system in the brain TME. The clinical potential of targeting the microenvironment through monotherapy or combination therapies is discussed, along with the impact of standard of care treatments on the brain tissue landscape.The brain tumor microenvironment (TME) is a critical regulator of cancer progression in primary and metastatic brain malignancies. The unique properties of the brain, including its immune privilege, distinct extracellular matrix (ECM), and the blood-brain barrier (BBB), necessitate a specific framework for designing targeted interventions. This review highlights the distinct features of the brain TME, such as the presence of brain-resident cell types, the BBB, and an immunosuppressive environment. Recent advances in therapeutically targeting the brain TME are discussed, emphasizing the importance of understanding the complex and interconnected microenvironmental landscape of brain malignancies to expand therapeutic strategies. The review focuses on gliomas, brain metastases, and medulloblastoma, highlighting the context-dependent roles of various immune cell types, the BBB, angiogenesis, and the ECM. It also explores the potential of targeting astrocytes, neurons, and the lymphatic system in the brain TME. The clinical potential of targeting the microenvironment through monotherapy or combination therapies is discussed, along with the impact of standard of care treatments on the brain tissue landscape.