Numerous neurological and psychiatric manifestations may accompany systemic lupus erythematosus (SLE). The many signs and symptoms of neuropsychiatric SLE (NPSLE) present a significant diagnostic and therapeutic challenge. Determination of the neuropsychiatric symptoms in SLE by American College of Rheumatology nomenclature has helped standardize clinical presentations. The multiplicity of proposed pathogenic mechanisms makes NPSLE complex and heterogeneous. The diagnosis can be made only on a case-by-case basis. Standard brain or spine MRI is the modality of choice for detecting and monitoring vascular ischemic lesions and demyelinating lesions. Treatment should be tailored for each patient. In progressive cases, most clinicians recommend 1 mg/kg/d of corticosteroids in divided doses. Open-label efficacy and safety has been shown with rituximab in refractory NPSLE. (J Musculoskel Med. 2009;26:127-135)