Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by multi-organ damage, and the neuropsychiatric complications of SLE (NPSLE) are associated with increased morbidity and mortality. In general, the diagnosis of NPSLE is difficult, because no single laboratory marker or imaging modality has been found which can serve as a gold standard, and the diagnosis is thus primarily clinical. The pathogenesis of NPSLE has not been fully elucidated. Focal symptoms are thought to more likely result from vascular lesions, whereas diffuse manifestations are more likely related to autoantibody- or cytokine-mediated impairment of neuronal function. However recent progress has provided evidence that a number of cytokines and chemokines, as well as autoantibodies, may be involved in the neuropsychiatric manifestations of SLE, because certain repertoires of cytokines/chemokines are detectable in the central nervous system of NPSLE patients during active disease. In addition, we have recently shown elevated levels of the soluble form of fractalkine, which is a newly described membrane-bound CX3C chemokine, in the cerebrospinal fluid of patients with active NPSLE. This review will discuss the involvement of cytokines and chemokines in the pathogenesis of NPSLE and the evaluation of their significance as a useful laboratory parameter of active neuropsychiatric disease.