In this manuscript, we review literature describing the neuropsychological and brain imaging characteristics of systemic lupus erythematosus (SLE) patients. The findings are compared and contrasted with multiple sclerosis (MS) studies, revealing similarities and differences of interest to clinicians and researchers. While cognitive impairment is somewhat less common in SLE than MS, the diseases share a similar cognitive profile with deficits most prominent on tests emphasizing the speed of information processing, working memory, and visual/spatial learning, and memory. In early or more mildly affected patients, diffuse white matter damage, which may not be apparent on conventional brain imaging, plays a major role in clinical presentation and cognitive testing. The causes of white matter damage are very different, however, and in later stages of the disease MS and SLE appear to give rise to different forms of cerebral pathology. MS may be characterized by increasing brain atrophy affecting especially the cortical and deep gray matter, at least after conversion to secondary progressive course. There is less evidence for neurodegenerative changes in SLE, but patients are increasingly at risk for cerebrovascular disease. We conclude by offering some suggestions for future clinical and imaging research.