© 2018 Informa UK Limited, trading as Taylor & Francis Group. Introduction: Primary central nervous system lymphoma (PCNSL) retains peculiar biological and clinical characteristics and a worse prognosis with respect to other comparable lymphomas. The need for high doses of chemotherapy to achieve valid drug concentrations in cerebral tissues and/or radiotherapy results in severe treatment-related toxicities, mainly neurologic, which are frequently as disabling as the disease itself. Areas covered: Several emerging combined therapies are addressed that focus on treating PCNSL. The prognosis has improved in the last years but several questions remain unanswered and the research of more effective therapies goes on. Information and data were obtained from direct authors’ experience and a PubMed search of recent peer-reviewed original articles, review articles, and clinical guidelines. Expert commentary: The substantial progress observed in PCNSL has to be ascribed to a carefully combination of standard chemotherapeutic drugs. High-dose methotrexate-based polychemotherapy followed by mainteinance therapy offers one of the best chances to control the disease. Major issues that deserve many efforts by researchers are the definition of optimal consolidation treatment and a shared management of specific conditions such as elderly population and intra-ocular localization. © 2018 Informa UK Limited, trading as Taylor & Francis Group.