Primary CNS lymphoma (PCNSL) is seen with increasing frequency in both immunocompetent and immunocompromised patients. Radiation therapy has historically been standard treatment for this disease, resulting in complete remissions in the majority of patients, but with most patients relapsing and dying of the disease in less than 2 years. The use of chemotherapy appears to be changing the natural history of this tumor, with significantly prolonged survival in some groups of patients. The optimal agents, doses, schedules, routes of administration, and need for radiation therapy, however, remain undefined. In this review, some of the questions regarding the management of PCNSL are addressed and recommendations are made regarding the design of future regimens.