This review article provides guidelines for the diagnosis, staging, and management of primary nervous system lymphoma based on the results of clinical trials conducted during the last decade. Recent progress in our understanding of the pathogenesis of primary nervous system lymphoma is summarized, and implications of these findings for the development of diagnostic tools and new therapeutic strategies are outlined. We performed a search of the PubMed database (National Center for Biotechnology Information) for articles on primary nervous system lymphoma published between 1970 and May 2005. Primary nervous system lymphoma affects the brain, eye, and meninges as well as cranial, spinal, and peripheral nerves. Although important lessons have been learned from the pathogenesis of extraneural non-Hodgkin's lymphoma, the unique organotropism of primary nervous system lymphoma remains poorly understood. Diagnosis is facilitated by modern imaging techniques and molecular markers. Clinically recognizable "precursors" may exist but frequently elude specific diagnosis. Insight into the peculiar pharmacokinetics of chemotherapy aimed at tumors within the nervous system has led to the development of methotrexate-based regimens that can achieve prolonged progression-free survival without the use of radiation. Long-term survival and, in selected cases, even a cure are possible in primary nervous system lymphoma. Treatment should be provided in specialized multidisciplinary centers. In spite of remarkable progress through methotrexate-based chemotherapy, the majority of patients experience relapse within a few years. Better diagnostic tools are required for earlier diagnosis and monitoring of treatment response. A deeper understanding of the pathogenesis of primary nervous system lymphoma may reveal new therapeutic targets.