Prevention of CNS metastases, even for LA-NSCLC patients with other sites of failure, will improve quality of life and, for patients controlled extracranially, will improve survival. Meta analyses performed on data from several Radiation Treatment Oncology Group (RTOG) studies have shown that longer survival for patients with LA-NSCLC treated with either radiation alone or radiochemotherapy is associated with an increased incidence of CNS metastases. Although the addition of chemotherapy to radiation therapy reduces extracranial distant metastases and improves survival it does not alter brain relapse rates. Even though the addition of modern targeted therapy using small-molecules or antibodies may further improve the outcome, the CNS remains the most common site of failure under targeted therapy, although no evidence for resistance in histological workups of metastases has been found. This emphasizes the urgent need for treatment directed at chemotherapeutically inaccessible (or dormant) micrometastases that are a priori dispersed within the brain. As the median time for relapse in the CNS is approximately 6 months after first-line therapy, the treatment of micrometastases should be meaningfully initiated even during or shortly after first-line therapy.