Cognitive impairment (CI) is one of the most prevalent neuropsychiatric syndromes. In Systemic Lupus Erythematosus (SLE) Patients often report CI as the most bothersome disease-related manifestation with a great impact on their quality of life. Nevertheless, studies focusing on CI remain scarce and no effective targeted therapy has been identified. We herein present murine models of CI in lupus with insights into the pathogenesis of this condition as well as the role of the renin angiotensin system in microglial activation. We will discuss the role of neuroimaging as a useful objective assessment tool describing our experience in previous and ongoing clinical trials of CI in SLE patients.