© Discovery Medicine. Type I interferons (IFNs) have a prominent role in many aspects of normal innate and adaptive immunity and autoimmunity. However, cell-type specific information about type I IFN expression and autocrine/paracrine signaling is sparse and mostly focused on non-lymphocyte and non-immune cell populations. A major function of B cells is cytokine production, but surprisingly, type I IFN production by B cells in systemic lupus erythematosus (SLE) has not been thoroughly investigated. This is due, in part, to the established view that plasmacytoid dendritic cells (pDCs) are the primary source of pathogenic type I IFN in lupus. Recent studies, however, have provided evidence to challenge this paradigm. Here, we discuss data supporting a new concept that the production of type I IFN, especially IFNβ, by early stage transitional B cells may be an important source of type I IFN to support autoreactive B cell development in lupus. These findings, if confirmed, may provide a new paradigm in designing and developing more effective therapies for preventing the formation of autoreactive B cells.