Postoperative radiation therapy (RT), either alone or in combination with chemotherapy, is the mainstay of treatment for primary and/or metastatic brain tumors. The majority of patients with brain tumors will have significant symptoms of their disease and of RT that will have a negative impact on their quality of life and neurocognitive function. The symptoms of brain tumors depend on tumor location. Radiation-induced brain injury is a complex and dynamic process involving all cells in the brain, including endothelial and oligodendroglial cells, astrocytes, microglia, neurons, and neuronal stem cells. The symptoms of radiation-induced brain injury may be acute, subacute, or chronic, occurring hours, days, weeks, months, and even years after exposure to radiation, the pathogenesis of which is oxidative stress and inflammation. At present, there are no effective preventive approaches for radiation-induced brain injury. Rather, the management of radiation-induced fatigue, changes in mood, and cognitive dysfunction involves a multidisciplinary approach using pharmacologic, behavioral, and rehabilitative therapies. Given the prevalence of brain neoplasms and the high incidence of the radiation-induced symptom cluster and brain injury, clinical research to address these important clinical problems is critical.