The use of radiotherapy alone to treat primary central nervous system lymphoma (PCNSL) does not produce the high local control and survival rates that it does in limited extranodal non-Hodgkin's lymphoma outside the central nervous system (CNS). Even with doses of whole brain radiation therapy (WBRT) to 40+20 Gy boost, the Radiation Therapy Oncology Group (RTOG) reported a local control rate of 39%. Seventy-nine percent of recurrences were in the 60 Gy region. The median survival was 11.6 months. This response to local radiotherapy is quite different from the response of non-CNS Diffuse Large Cell Lymphoma where doses of 30-40 and >40 Gy have a 75-90% local control rate. Neither systemic lymphoma nor PCNSL have a classic radiotherapy dose response. For PCNSL there appears to be a threshold dose that ranges in the literature between 30 and > 50 Gy with a median of 40 Gy. Therefore, when radiotherapy is combined with chemotherapy that crosses the BBB, WBRT and/or boost doses may be able to be decreased, especially in patients achieving a complete response. Promising data from the Centre Leon Berard suggest that this is possible. When such chemotherapy was combined with intrathecal chemotherapy and 20 Gy WBRT, they obtained a 56% actuarial 5 year survival rate. Confirmation of single institution reports of favorable results such as these are needed. Cooperative group and intergroup trials are needed to define optimal therapy.