Neurologists and rheumatologist are often called to evaluate central nervous system (CNS) manifestations in patients with suspected or definite systemic lupus erythematosus (SLE). The manifestations are highly diverse and often have major prognostic consequences. The major difficulties are to determine if the given manifestation is primarily due to SLE activity in the brain, or a consequence of metabolic disturbances, infection, or corticosteroid use. The true incidence of CNS manifestations attributable to SLE is not entirely clear, but several studies show prevalence rate between 15-75%, depending on different methods and classification criteria applied. This paper has the objective to review the main clinical manifestations according to American College of Rheumatology (ACR) criteria, possible etiological mechanisms and neuroimaging features associated with these manifestations. We further discuss the most important tools that can help bedside diagnosis.