Studies of the immunopathogenesis of systemic lupus erythematosus (SLE) have traditionally focused on the mechanisms of generation of the characteristic autoantibodies reactive with nucleic acid-containing intracellular particles and the contribution of autoantibody-autoantigen immune complexes to the inflammation and tissue damage that result in the clinical manifestations of lupus. The recent recognition of the central role of type I interferons (IFN) in this classic autoimmune disease has led to new understanding of the significant role of the innate immune system in the predisposition to and amplification of autoimmunity and tissue damage. Ongoing studies are defining the genetic factors, immune stimuli, and molecular pathways that contribute to production of IFN and induction of its downstream targets in SLE. Investigations of lupus patients and murine lupus models suggest a primary role for type I IFNs in systemic autoimmunity and support the case for therapeutic inhibition of the IFN pathway in lupus and possibly other systemic autoimmune diseases.