Primary central nervous system lymphoma is a rare and aggressive extranodal non-Hodgkin lymphoma restricted to the brain, spinal cord, cerebrospinal fluid, and eyes. Optimization of treatment including high-dose methotrexate-based chemotherapy followed by consolidation therapy in the form of autologous stem cell transplant or whole-brain radiation leads to improved survival. However, several patients do not respond to upfront therapy and the relapse risk is high. Additionally, there is a risk of delayed neurotoxicity, particularly in older patients. Recent molecular insights underlying the pathophysiology of PCNSL have led to the development of clinical trials involving targeted therapies and immunotherapies for salvage.