Primary central nervous system lymphoma (PCNSL) is an uncommon subtype of extranodal non-Hodgkin lymphoma (NHL) with less than 1500 cases annually. Incidence of PCNSL has remained stable in the post–highly active antiretroviral therapy era, owing to increasing incidence in elderly, immunocompetent patients. Most PCNSL is diffuse large B cell in origin, with less frequent involvement of T-cell and Burkitt lymphoma. Secondary central nervous system lymphoma is more likely to occur in the relapsed setting of a systemic NHL. Methotrexate forms the backbone of management for prophylaxis and treatment of disease. Treatments are currently under investigation for both disease entities.