Neuropsychiatric systemic lupus erythematosus (NPSLE), comprised of numerous, complex central and peripheral nervous system symptoms, poses significant challenges at the bedside and even more in the laboratory. A consideration of pathologic mechanisms stratified by anatomic location allows enhanced understanding of diverse symptomatology, kinetics of disease, symptom reversibility, and regional brain vulnerability. This chapter presents the mechanisms of injury to brain vasculature, brain parenchyma, and the peripheral nervous system, with a discussion of the blood-brain barrier (BBB) included to inform studies of damage to brain parenchyma. Insults to blood vessels are often mediated by endothelial cell activation. Moreover, the BBB links endothelial or vascular damage to central nervous system (CNS) damage. Activated endothelial cells can lead to vasculitis, but more often to alterations in BBB integrity that permit circulating autoantibodies and inflammatory molecules to gain access to vulnerable cellular components of the CNS. Increased understanding of the BBB and its role in regulating access to the CNS has led to an appreciation of its permissive and preventive role in pathologic conditions. Once the BBB has been disrupted, there is potential for direct toxicity to cells of the CNS by autoantibodies and cytokines. New information about autoantibodies and cytokines suggest they contribute to the pathogenesis of the diffuse nervous system disorders through neuronal death and dysfunction. Vasculopathy and clotting abnormalities, also the result of autoantibodies and inflammation, contribute strongly to the focal nervous system disorders.