Nervous system disease in systemic lupus erythematosus (SLE) is manifested by a wide variety of clinical manifestations. Despite the development of a universal classification for neuropsychiatric (NP) lupus in 1999, there continues to be considerable variability in the reported prevalence of NP syndromes between different lupus cohorts. Due to the lack of specificity of individual NP manifestations, non-SLE causes such as complications of therapy and co-morbidities must be considered in advance of attributing the event to one or more primary immunopathogenic mechanisms. These include intracranial microangiopathy, autoantibodies to neuronal and non-neuronal antigens, and the generation of proinflammatory cytokines and mediators. The diagnosis of NP-SLE remains largely one of exclusion and is approached in individual patients by thorough clinical evaluation, supported when necessary by autoantibody profiles, diagnostic imaging, electrophysiologic studies and objective assessment of cognitive performance. Given the diversity in clinical manifestations, the management is tailored to the specific needs of individual patients. In the absence of controlled studies, the use of symptomatic therapies, immunosuppressives, anticoagulants and non-pharmacologic interventions is supported by case series and clinical experience.