In recent years, the study of systemic lupus erythematosus (SLE) patients has revealed a central role for type I interferon (IFN) in disease pathogenesis. IFN induces the unabated activation of peripheral dendritic cells, which select and activate autoreactive T cells rather than deleting them, thus failing to induce peripheral tolerance. IFN also directly affects T cells and B cells. Furthermore, immune complexes binding to FcgammaR and Toll-like receptors provide an amplification loop for IFN production and B-cell activation in SLE. Polymorphisms in genes that control IFN production or its downstream signaling pathway, such as IRF5, might be responsible for some of these alterations. This novel information is leading to the development of IFN antagonists as a potential therapeutic intervention in SLE, thus bringing hope to SLE patients.