The diagnosis of lymphoma of the central nervous system (CNS) has been facilitated by advances in neuroimaging and laboratory analysis of cerebrospinal fluid. The most common form of central nervous system CNS involvement in non-Hodgkin's lymphoma (NHL) is leptomeningeal disease. After a diagnosis is established, the use of intrathecal or systemic chemotherapy and radiotherapy can improve survival and palliate symptoms. High-dose systemic chemotherapy with hematopoietic stem cell transplantation is an important treatment option at central nervous system relapse of NHL and for primary CNS lymphoma. The prognosis for disease-free survival and cure is better for patients who have treatment of CNS disease before transplantation than for patients who have active central nervous system disease at the time of transplant.