Systemic lupus erythematosus (SLE) is a chronic systemic autoimmune illness characterized by autoantibodies directed at nuclear antigens that cause clinical and laboratory abnormalities, such as rash, arthritis, leukopenia and thrombocytopenia, alopecia, fever, nephritis, and neurologic disease. Most or all of the symptoms of acute lupus are attributable to immunologic attack on the affected organs. Many complications of long-term disease are attributable to both the disease and its treatment. Intense sun exposure, drug reactions, and infections are circumstances that induce flare; the aim of treatment is to induce remission. This chapter is divided into sections dealing with SLE’s definitions; epidemiology; pathogenesis; disease classification, diagnosis, and differential diagnosis; and treatment. The section about pathogenesis discusses autoantibodies, abnormal innate and adaptive immunity, genetic susceptibility, infections, female predominance, and the complications of chronic illness. The discussion of disease classification, diagnosis, and differential diagnosis takes into account systemic signs and symptoms, skin and mucosal involvement, pulmonary involvement, cardiovascular involvement, musculoskeletal involvement, gastrointestinal and hepatic involvement, hematologic and ontologic involvement, neuropsychiatric involvement, renal involvement, special presentations, and indices of disease activity and damage. The discussion of treatment covers active disease, treatment of antiphospholipid syndrome (APS), and SLE during pregnancy. Figures illustrate important features of the pathogenesis of systemic SLE, malar rash, rash of subacute cutaneous lupus erythematosus annular type, discoid lupus rashes, lesions of discoid lupus erythematosus, oral ulcers, pleural effusion due to SLE, gray matter transverse myelitis involving the conus medularis, and selected kidney biopsy histology in lupus nephritis. A graph shows the incidence of SLE based on sex, age, and race. Tables detail types of human lupus erythematosus other than SLE, subtypes of drug-induced lupus erythematosus, American College of Rheumatology revised criteria for the classification of SLE, clinical and immunologic criteria in the Systemic Lupus International Collaborating Clinics classification criteria, neuropsychiatric SLE attributed to SLE, the International Society of Nephrology/Renal Pathology Society classification of lupus nephritis, revised classification criteria for APS syndrome, SLE management goals, “standard of care” therapies for SLE, and management of proliferative lupus nephritis and nephrotic membranous lupus nephritis. This chapter contains 10 highly rendered figures, 10 tables, 194 references, 1 teaching slide set, and 5 MCQs.