Abstract: Primary central nervous system lymphoma (PCNSL) is a subtype of extranodal non-Hodgkin's lymphoma that only involves brain parenchyma, spinal cord, eyes, cranial nerves and meninges, and no part other than central nervous system (CNS) is involved. At present, high-dose methotrexate-based chemotherapy became standard of care, which combine with high-dose chemotherapy, autologous stem cell transplantation (auto-HSCT) or reduced whole brain radiation therapy (WBRT). However, it results in low remission rate and severe side effects. Studies have shown that 10% of patients are resistant to primary induction chemotherapy, and even if the treatment is effective, 50% would still relapse. Recently, novel insights from genetics and molecular analysis into this unique disease have been elucidated and have paved the way for the investigation of rational approaches. A promising prospect of small molecular drugs and targeted therapy has developed, which is expected to reduce side effects, improve the remission rate of patients and prolong life. This review will give an overview of the new treatment of PCNSL.