Neurological and psychiatric disorders are common in patients with systemic lupus erythematosus (SLE). While several pathogenetic mechanisms are thought to be involved, among of the most challenging and best investigated are antibodies against the N-methyl-D: -aspartate (NMDA) receptor subtypes 2a and 2b (anti-NR2 antibodies). This review summarizes the most relevant mechanisms for neuropsychiatric (NP) involvement in SLE (NPSLE) with special emphasis on the role of anti-NR2 antibodies and provides an overview of published articles on anti-NR2 antibodies and brain involvement as of May 2011. In mice, neuronal cell death occurs when anti-NR2 antibodies gain access to the brain, either by injection directly into the brain, or by systemic immunization and abrogation of the blood-brain barrier. Either impaired memory and hippocampal atrophy, or emotional disturbances and atrophy of the amygdala follow, seemingly dependent on the method used for disruption of the blood-brain barrier. Recent studies indicate that the effect of anti-NR2 antibodies is dose dependent; at low concentrations they alter synaptic function; at higher concentrations they can cause neuronal cell death by apoptosis. An association between anti-NR2 antibodies and NPSLE has been confirmed in 6 out of 13 human studies; the manifestations are primarily of diffuse cerebral character.