Primary central nervous system lymphoma (PCNSL) is a rare form of non-Hodgkin lymphoma (NHL) that is restricted entirely to the brain, leptomeninges, eyes, and rarely the spinal cord. It typically presents with focal neurologic symptoms and is characterized by diffuse infiltration of the brain. Corticosteroids are useful for symptomatic treatment but can interfere with definitive pathological diagnosis. PCNSL is radiosensitive and responds to whole-brain radiotherapy. The use of preirradiation high-dose methotrexate-based regimens has significantly improved response rates and patient survival. Longer survival, however, is often marred by devastating neurotoxicity to which the elderly are particularly susceptible. Newer regimens aim to minimize such toxicity while maintaining the survival benefit of combined modality treatment.