Drs. Cooper and Rotow review the challenges of CNS involvement in HER2+ NSCLC, emphasizing the importance of baseline and ongoing brain imaging, and the emerging understanding of CNS penetrance for HER2-targeted therapies. They explore strategies for managing brain metastases, including balancing local therapies, including radiation with systemic treatments, and highlight the need for multidisciplinary approaches and further research on CNS activity in clinical trials.