Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease characterized by diverse clinical manifestations in association with widespread immune cell dysfunction. Because of the complexity of SLE, biomarkers have been important in delineating disease mechanisms as well as evaluating patients and determining therapy. Basic and translational research has identified a large number of immune abnormalities in SLE, although only a few are commonly used as biomarkers. Of these, antinuclear antibodies (ANAs) are a hallmark of SLE but are not specific for this disease. In contrast, antibodies to DNA and an RNA-protein complex called the Sm antigen represent markers for patient classification and are specific markers for lupus. The formation of immune complexes (ICs) between ANAs and their cognate antigens is an important mechanism for disease, provoking nephritis as well as immune cell activation to produce type 1 interferon. Direct determination of IC levels has not been informative, although assays of complement levels by a number of approaches provide important information on disease activity. Other biomarker assays are important for evaluating the occurrence of the antiphospholipid antibody syndrome (APS), which can lead to arterial and venous thrombosis as well as pregnancy loss. These assays can detect antibodies to cardiolipin as well as a protein called β2-glycoprotein 1; functional assays of clotting allow determination of lupus anticoagulants. Among newer approaches, determination of the interferon signature by gene expression assays provides important information on the role of cytokines in pathogenesis and points to a therapeutic target. In view of the impact of nephritis on morbidity and mortality, a variety of assays can be used to assess renal disease activity. Thus, evaluation of lupus entails biomarkers specific for underlying disease mechanisms as well as biomarkers for organ inflammation and damage.