A major advance in the treatment of primary central nervous system lymphoma (PCNSL) was made when the addition of chemotherapy to radiotherapy was shown to improve patient survival significantly. However, few chemotherapeutic agents are able to cross the blood-brain barrier. New therapeutic approaches in PCNSL are based on: the treatment of systemic non-Hodgkin's lymphomas with monoclonal antibodies and intensive chemotherapy followed by hematopoietic stem cell rescue, new chemotherapeutic agents with central nervous system penetration, or blood-brain barrier disruption to enhance drug delivery to the brain. This article discusses the rationale and results of these innovative approaches.