Management of central nervous system (CNS) involvement still remains one of the most challenging problems in systemic lupus erythematosus (SLE). The best available evidence for the treatment of CNS lupus is largely based on retrospective series, case reports and expert opinion. Current therapy is empirical and tailored to the individual patient. Symptomatic, immunosuppressive and anticoagulant therapies are the main strategies for the management of CNS lupus. The choice depends on the most probable underlying pathogenic mechanism and the severity of the presenting neuropsychiatric symptoms. Thrombotic and nonthrombotic CNS disease needs to be differentiated and requires different management strategies. However, this is often challenging since many, if not most CNS manifestations, may be due to a combination of different pathogenic mechanisms and multiple CNS events may occur in the individual patient. Patients with mild manifestations may need symptomatic treatment only, whereas more severe acute nonthrombotic CNS manifestations may require pulse intravenous cyclophosphamide. Plasmapheresis may also be added in patients with more severe illness refractory to conventional treatment. Recently, the use of intrathecal methotrexate and dexamethasone has been reported in a small series of patients, with a good outcome in patients with severe CNS manifestations. Anticoagulation is warranted in patients with thrombotic disease, particularly in those with the antiphospholipid syndrome (APS). This article reviews the clinical approach to therapy in patients with CNS lupus.