Full manifestation of mouse lupus, similar to the human disease in its severe form, is characterized by elevated antinuclear autoantibody levels and the development of kidney disease. Considerable evidence supports a genetic basis for lupus. The functional dissection of susceptibility loci in multigenic mouse models of lupus has provided insight into the immune abnormalities associated with autoantibody production and other processes critical for inflammation and damage in the kidney. The elucidation of models with single-gene manipulations has also identified immune mechanisms in the pathway to lupus. Recent advances have challenged previously accepted truths and new layers of complexity have become apparent.