Neuropsychiatric Systemic Lupus Erythematous comprises several neurologic and psychiatric manifestations attributable to Lupus Erythematous Systemic. Diagnosis implies exclusion of non- Systemic Lupus Erythematous -related diseases that might mimic the same symptoms and should be prompt in order to avoid delaying the treatment. Treatment is dictated by the underlying pathogenesis and includes immunosuppression and/or anti-platelet agents/anticoagulation. We report four cases of Neuropsychiatric Systemic Lupus Erythematous, illustrating how challenging it can be to diagnose and treat these patients.