Two challenges need to be addressed to improve the outcome of patients with primary central nervous system lymphoma. The first challenge is to develop therapies that result in less toxicity and improved long-term outcome. The second challenge is to develop interventions to help those patients who develop treatment-related neurotoxicity; ongoing collaborative efforts are required to improve communication and understanding of this complication. Long-term follow up of prospective therapeutic studies should report on both disease control and the development of neurotoxicity. New protocols should include prospective longitudinal measures of neurocognitive function.