Signs and symptoms of neuropsychiatric systemic lupus erythematosus (NPSLE), as defined by the American College of Rheumatology case definitions, occur commonly in adolescents with lupus. Thought and mood disorders are more difficult to identify than specific central or peripheral nervous system injuries. Furthermore, thought and mood disorders must be differentiated from other causes, including traumatic, metabolic, endocrinologic, toxic, and infectious etiologies. It is also important to recognize that primary mood and thought disorders can present in adolescence. The effects of chronic disease during adolescent development can also trigger alterations in mood and cognitive function. This article reviews proposed etiologies of injury, diagnosis, and differential diagnosis of NPSLE. At this time, no specific test identifies NPSLE as the cause of mood and cognitive changes; however, current efforts to standardize evaluation of cognitive function and develop imaging techniques that identify anatomic brain changes will improve the practice of rheumatology.