Neuropsychiatric events are common in patients with systemic lupus erythematosus (SLE), but less than one-third of these events can be directly attributed to SLE. Increased generalized SLE disease activity or damage, previous or concurrent major neuropsychiatric SLE (NPSLE) events, and persistently positive moderate-to-high antiphospholipid antibody titers are established risk factors, and their presence could facilitate proper attribution to the disease itself. Diagnostic evaluation is guided by the presenting manifestation; MRI is used to visualize brain or spinal pathologies. For neuropsychiatric events believed to reflect an immune or inflammatory process, or when these events occur in the context of active generalized disease, evidence (primarily from uncontrolled studies) supports the use of glucocorticoids alone or in combination with immunosuppressive therapy. Antiplatelet and/or anticoagulation therapy is recommended for NPSLE manifestations related to antiphospholipid antibodies, especially for thrombotic cerebrovascular disease. For the future, we anticipate that novel biomarkers and advanced neuroimaging tests will better define the underlying pathologic mechanisms of SLE-related neuropsychiatric disease, and help guide therapeutic decisions.