Murine experimental studies demonstrate that the gender bias in the prototypical autoimmune disease systemic lupus erythematosus (SLE) may be influenced by sex hormones and genetic factors. The female hormone estrogen, as well as prolactin, act as immunostimulators that accelerate the onset of disease and cause early mortality in the NZB/W F1 murine model of lupus. Both estrogen and prolactin induce lupus in mice which are not spontaneously autoimmune by impairing the deletion of autoreactive B cells and skewing their maturation toward marginal zone phenotype and follicular phenotype, respectively. Blockade of estrogen and inhibition of pituitary prolactin secretion with selective estrogen receptor modulators and bromocriptine, respectively, provide a therapeutic effect in lupus-prone mice, as well as in mice with estrogen or prolactin-induced lupus. The effects of the hormones are genetically determined, and it has been established that certain genetic factors such as the lupus susceptibility locus Sle3 synergize with prolactin to allow the development of lupus. In contrast to female sex hormones, androgens have an ameliorative effect on disease activity in lupus-prone mice. Alterations of specific gender-associated genetic factors are linked to murine lupus. The Yaa mutation on the Y chromosome of lupus-prone BXSB male mice contains a duplication of a set of genes from the X chromosome. One of these duplicated genes encodes for TLR7, and the extra copy of this gene leads to a doubling of the RNA receptor and makes the BXSB mice predisposed to an autoimmune response to the body's own RNA. Our review of the impact of gender via sex hormones and explicit genetic factors in the pathogenesis of murine lupus suggests that a better understanding of mechanisms underlying sexual dimorphism of the immune system may lead to the development of novel therapeutic approaches to lupus.