The incidence of primary central nervous system lymphoma (PCNSL) has risen significantly in both the immunocompetent and immunosuppressed populations in the past two decades. PCNSL usually is restricted to (but disseminated within) the central nervous system, including the leptomeninges and eyes. The addition of chemotherapy to radiation therapy has improved patient survival significantly over radiation therapy alone, but the prognosis of PCNSL is not as good as that for comparable systemic non-Hodgkin's lymphomas. The behavior of PCNSL in the immunosuppressed population differs from that in immunocompetent patients, creating specific diagnostic and therapeutic challenges.