Widespread chronic pain, fatigue, and distress do not represent risk factors for future systemic lupus erythematosus (SLE) or other autoimmune syndromes. On the other hand, SLE seems to be a significant risk factor for fibromyalgia (FM). Up to 47% of SLE patients fulfill FM criteria. SLE patients with concomitant FM are often highly symptomatic and dysfunctional. The presence of FM symptoms in SLE patients, however, does not predict more extensive organ involvement or lupus activity. The high concordance of SLE with FM suggests common mechanisms related to pain and distress in both patient groups. Recent research suggests involvement of N-methyl-D-aspartate (NMDA) and neurokinin receptor systems. Thus, autoimmune activity against these receptor systems in SLE patients could result in pain, cognitive defects, and chronic pain states including FM. Conversely, treatment of SLE-FM patients with inhibitors of NMDA or neurokinin receptors may prevent or alleviate cognitive abnormalities and chronic pain, as well as FM.