Prolonged exposure of the immune system to type I interferons (IFN-alpha/beta/omega) in patients receiving IFN-alpha therapy frequently results in development of autoantibodies and autoimmune disease. This is attributed to the many immunostimulatory effects of these cytokines. Patients with the autoimmune disease systemic lupus erythematosus (SLE) have an ongoing IFN-alpha production. Recent studies of SLE demonstrated the presence of endogenous IFN-alpha inducers, acting specifically on natural IFN-alpha producing cells (NIPC), often termed plasmacytoid dendritic cells (PDC). These IFN-alpha inducers were potent, present at the blood level, and characterized as immune complexes that contained DNA and IgG as essential components. They were considered a likely reason for the activated IFN-alpha production in SLE, which, in turn, might be an important etiopathogenic factor. Here, we briefly review the biology of the type I IFN system, with emphasis on inducers, producing cells (especially NIPC/PDC), IFN-alpha actions, and target immune cells, which might be relevant in SLE. Based on such information and results from studies in SLE patients, we propose a hypothesis that explains how NIPC/PDC become activated and play a pivotal etiopathogenic role in SLE and perhaps also other autoimmune diseases. This hypothesis furthermore indicates new therapeutic targets.