Primary central nervous system lymphoma (PCNSL) is a rare, aggressive form of lymphoma, accounting for approximately 1-2% of all cases of lymphoid neoplasms in Japan. The current standard treatment for these tumors, which arise in pharmacological sanctuaries isolated by the blood brain barrier, is chemo-radiation with high-dose methotrexate (3g/m(2)) and cytarabine (3g/m(2)) followed by whole brain radiotherapy (WBRT) (45Gy). To overcome the limitations of and neurotoxicities associated with WBRT, several novel therapeutic strategies have been developed. These include either upfront intensive chemotherapy with high-dose alkylating agents combined with stem cell transplantation or less toxic immunochemotherapy with molecular targeted agents such as anti-CD20 monoclonal antibody. The roles of these therapies for PCNSL are being assessed in ongoing randomized clinical trials and will be further explored in the future.