Type I interferons (IFN-I) are cytokines acting ubiquitously by autocrine or paracrine mechanisms in order to trigger cell defense programs. The transcription of the genes coding for IFN-I is induced by Toll-like receptors (TLR) activation and signaling. The signal transduction pathways initiated by IFN-I upon engagement with their cell membrane receptors are dependent on infectious factors such as viral ds-RNA, but also on intrinsic activators and down-regulators, and lead to either inflammation or cell apoptosis. Many viruses have developed strategies aimed at blocking these pathways and attempts have been made to regulate specific pathway components by several therapeutic means in order to treat various viral diseases such as hepatitis and AIDS. It has become more and more apparent however that IFN-I are also cytokines with pleiotropic effects on many aspects of cell physiology and function, induced by noninfectious triggering agents. In particular, the pathways play major roles in the cross-talk between innate and adaptive immunity. Despite the fact that a possible viral etiology of autoimmune diseases is still under debate, recent converging data indicate that the IFN-I pathways are selectively and specifically deregulated in many autoimmune diseases, including type I diabetes, systemic lupus erythematosus, rheumatoid arthritis and multiple sclerosis. This article presents our current understanding of the TLR / IFN-I pathways and reviews their deregulations in autoimmune diseases with an aim at identifying new and specific therapeutic targets.