Type I IFN (IFN-I) was firstly described in 1957 as a soluble factor responsible for viral resistance in vitro. Today, it is well known that the IFN-I family comprises a wide number of cytokines with different modulatory effects on angiogenesis, cell growth, fibrosis, and apoptosis. However, one of the most important functions of IFN-I is the capability to trigger a complex array of cellular responses that result in a host-protective antiviral response. For this reason, IFN-I can be considered a "director" of protective immune responses. The recent finding of the so-called interferon signature in patients suffering from different autoimmune diseases has underlined its possible role in the pathogenesis of these diseases. On the other hand, IFN-alpha/beta is reported to be efficacious in the treatment of some autoimmune and infectious diseases not responsive to conventional therapy. On these occasions, the treated patients often start or increase autoantibody production supporting the role of IFN as inducer of an autoimmune response. In this review, we will underline recent acquisitions about IFN-I biology, with a focus on the relevance of the induction of some autoimmune diseases, such as systemic lupus erythematosus, systemic sclerosis, rheumatoid arthritis, dermato/polymiositis, and Sjogren's syndrome.