Data generated using high-throughput DNA microarrays are changing the way we think about systemic lupus erythematosus (SLE). The identification of an interferon gene-expression signature in the majority of patients with SLE, especially those with severe SLE, has stimulated substantial interest in targeting the interferon pathway for the treatment SLE and has catalyzed new inquiries into the utility of interferon signaling as a diagnostic and prognostic biomarker for SLE. As these genomic datasets enlarge and mature, new signatures are being identified that implicate other pathways dysregulated in SLE, including oxidative phosphorylation, immunoglobulin production and granulocyte maturation. Highly anticipated longitudinal studies will be important in defining how this information will ultimately change the way SLE is managed in the clinical setting.