The pathogenesis of systemic lupus erythematosus (SLE) can be divided into discrete stages. Both environmental and genetic factors contribute to the development of the disease. Triggers such as hormones, microbes, diet, and drugs can elicit autoimmunity. These elements and epigenetic changes drive a sustained loss of tolerance and the spread of autoimmunity. Subsequently, immune-complex deposition and autoantibody-mediated tissue damage can cause chronic inflammation and irreversible damage in end organs. Active SLE is characterized by a remarkably homogeneous gene expression pattern with overexpression of interferon (IFN)-induced genes, which is the so-called IFN signature. The type I IFN system has been suggested as a driving force behind the disease, that is, nucleic acids derived from apoptotic cells and neutrophil extracellular traps provide the critical ligands to drive expression of type I IFNs from plasmacytoid dendritic cells via toll-like receptors. Type I IFNs increase the production of B cell-activating factor (BAFF) by macrophages and dendritic cells. BAFF is a cell survival and maturation factor for B cells. Type I IFNs also decrease regulatory T cell function. Both T cells and B cells participate in autoreactivity, with B cells ultimately producing autoantibodies. Interleukin 17 production by T cell also contributes to organ infiltration by neutrophils.