The pathogenesis of the neuropsychiatric manifestations of systemic lupus erythematosus (SLE) remains an enigma. The observation that many of the lymphocytotoxic antibodies in SLE are also brain-reactive has led to the hypothesis that central nervous system (CNS) lupus, like the autoimmune hematologic manifestations of SLE, is due to the direct effects of autoantibodies to cell membrane antigens. Studies of neuron-reactive antibodies in SLE sera and cerebrospinal fluid support that hypothesis and suggest that the diffuse neuropsychiatric manifestations require the co-existence of serum antibodies to nerve cells and an alteration in the blood-brain barrier that allows those antibodies to enter the CNS.