Systemic lupus erythematosus (SLE) is an autoimmune inflammatory condition that may involve multiple organ systems. Although the antinuclear antibody (ANA) test is positive in nearly every case of SLE, it is not specific for this disease and must be interpreted in the appropriate clinical context. Key features that warrant ANA testing include unexplained multisystem inflammatory disease, symmetric joint pain with inflammatory features, photosensitive rash, and cytopenias. ANA staining patterns and more specific autoantibody testing may be helpful in diagnosis of suspected SLE or ANA-associated disease. For patients with nonspecific symptoms, such as malaise and fatigue, ANA testing is of limited value.