Recommendations regarding the current therapy of primary brain lymphoma (NHL-CNS) take into account the occurrence of this tumor in immunocompetent and immunosuppressed hosts. Immunohistochemical evaluation of biopsy material or spinal fluid provides the diagnosis in 90% of patients. For the immunocompetent, pre-irradiation intra-venous or intra-arterial chemotherapy with Methotrexate alone or in combination with other agents is provided to treat tumor within multiple brain sites. Subarachnoid deposits are treated with Methotrexate by intrathecal administration. Radiation is provided after chemotherapy and for the treatment of vitreal/retinal deposits or symptomatic lesions within the spinal axis. The therapy of recurrent NHL-CNS makes use of intravenous Methotrexate or high dose Cytosine Arabinoside. Immunosuppressed patients respond to reduction of immunosuppressive medication. The therapy of NHL-CNS in the AIDS patient makes use of corticosteroids followed by cranial irradiation. A discussion of emerging trends in the therapy of NHL-CNS in the AIDS and non-AIDS population is provided.