There is now ample evidence that multiple genes are involved in the pathogenesis of systemic lupus erythematosus (SLE) in New Zealand mice. However, it also became evident that SLE is a syndrome in which each autoimmune feature is separately controlled by a limited number of major genes although some common genes do play a role in different autoimmune features. The data obtained by genetic analyses of murine lupus are a most useful guide for studies on autoimmunity, as related to (1) the type or subset of immune cells expressing each autoimmune disease gene; (2) how each gene or the cell (in which the gene is activated) plays a role in the etiopathogenesis of the disease; and (3) how the gene actions can be manipulated. Data on aspects of the genetic and cellular basis of murine lupus, particularly as related to the anti-DNA antibody synthesis in the (NZB X NZW)F1 hybrid mice are presented based on studies done in our laboratories.