Gene variants in mice that have strong, Mendelian effects on autoimmune susceptibility have been one of the most productive entry points for identifying genes and processes regulating human autoimmunity. With the tools now available to map and identify new mouse Mendelian gene variants, the handful of spontaneous mutations accumulated over several decades have all been identified, and the main bottleneck lies in producing new Mendelian immune variants. We outline here a strategy to generate large sets of functional variants in genes controlling lupus and humoral immunity, based upon limited variation of the mouse genome sequence with the chemical mutagen, ENU, combined with a set of sensitive immunological screens.