Cognitive disturbances, mood disorders and fatigue are common in SLE patients with substantial adverse effects on function and quality of life. Attribution of these clinical findings to immune-mediated disturbances associated with SLE remains difficult and has compromised research efforts in these areas. Improved understanding of the role of the immune system in neurologic processes essential for cognition including synaptic plasticity, long term potentiation and adult neurogenesis suggests multiple potential mechanisms for altered central nervous system function associated with a chronic inflammatory illness such as SLE. This review will focus on the biology of cognition and neuroinflammation in normal circumstances and potential biologic mechanisms for cognitive impairment, depression and fatigue attributable to SLE.