Autoimmune diseases include a wide spectrum of disorders, which have been divided into systemic and organ-specific disorders. Lupus, the prototypic systemic autoimmune disease, is characterized by female predominance, multiorgan pathology, and autoantibodies, primarily directed against nuclear antigens. The disease is heterogeneous, with variable organ involvement, serology, and clinical course. Susceptibility to lupus is inherited as a polygenic trait with added contributions from environmental and stochastic variance. Concerted efforts have recently been made by several laboratories to define the genetic basis of this disease in predisposed mice and humans. The identification of the Fas/FasL defects in lpr and gld lupus mice was the first example of spontaneous mutations of apoptosis-promoting genes being associated with systemic autoimmunity. This research was instrumental in clarifying the roles of these genes in tolerance and immunoregulation, and in extrapolating these results to other autoimmune diseases, as well as cancer and transplantation. To these findings have been added those from transgenic and gene knockout mouse studies that have helped to define the systemic autoimmunity-inducing or -modifying effects of specific genes in normal background and lupus-congenic mice. In addition, the findings from genome-wide searches have begun to identify predisposing loci (and ultimately genes) for the spontaneous lupus-like diseases in various mouse strains and in humans. The emerging picture is that multiple genetic contributions can independently lead to systemic autoimmunity in mice, which reinforces the view that human lupus may be similarly composed of diverse genotypes. This complexity underscores the importance of defining the predisposing alleles and mechanisms of action, an undertaking that is certainly feasible given current technologies and future advances in the definition of mammalian genomes.