Despite recent advances in diagnosis and treatment, the prognosis of primary CNS lymphoma (PCNSL) and CNS relapse of systemic non-Hodgkin lymphoma remains poor, and the optimal treatment is yet to be defined. This review presents an overview of the current status of CNS lymphoma treatment. Treatment options include radiotherapy alone, intravenous conventional chemotherapy alone, intrathecal chemotherapy, high-dose chemotherapy with autologous stem cell transplantation, combined modality treatment (i.e., chemotherapy plus radiotherapy), immunotherapy, radioimmunotherapy and ocular radiation and/or chemotherapy for intraocular lymphoma. High-dose methotrexate remains an essential part of most first-line treatments for PCNSL and CNS relapse of systemic non-Hodgkin lymphoma. Treatment standardization is hampered by the rarity of the disease and the difficulty of conducting trials with a higher number of patients. However, a recently closed Phase III/IV trial will most likely define the role of adjuvant whole-brain radiation treatment in PCNSL. Future directions in the management of PCNSL and CNS relapse of systemic lymphoma may include treatment stratification according to patient age and clinical and biological prognostic factors.