The prevailing notion is that lupus nephritis is mediated by autoantibodies, particularly those that bind to DNA and/or glomeruli. However it has become apparent that the development of immune-mediated renal disease is contingent upon additional factors including innate stimuli and host genetics. The purpose of this review is to evaluate our current understanding of three factors that can potentially influence immune-mediated renal disease: (1) Anti-glomerular/DNA antibodies (Abs), (2) Innate triggers, including Toll-Like Receptor (TLR) stimulation, and (3) the genetic makeup of the host.