Considerable evidence suggests that the development of systemic lupus erythematosus (SLE) has a strong genetic basis. Recent studies have emphasized that this disease, like other autoimmune diseases, is a complex genetic trait with contributions from major histocompatibility complex (MHC) genes and multiple non-MHC genes. Etiologic genes in these disorders determine susceptibility, and no particular gene is necessary or sufficient for disease expression. Studies of murine models of lupus have provided important insight into the immunopathogenesis of IgG autoantibody production and lupus nephritis, and genetic analyses of these mice overcome certain obstacles encountered when studying patients. Genome-wide linkage studies of different crosses have mapped the position of at least 12 non-MHC disease-susceptibility loci in the New Zealand hybrid model of lupus. Although the identity of the actual genes is currently unknown, recent studies have begun to characterize how these genetic contributions may function in the autoimmune process, especially in terms of their role in autoantibody production. Studies of MHC gene contributions in New Zealand mice have shown that heterozygosity for particular haplotypes greatly increases pathogenic autoantibody production and the incidence of severe nephritis. The mechanism for this effect appears to be genetically complex. Studies in human SLE have mostly focused on the association of disease with alleles of immunologically relevant genes, especially in the MHC. Associations with various complement component deficiencies and an allele of a particular Fc gamma receptor gene (FCGR2A) also have been described. In a diversion from previous association studies, a recent directed linkage analysis of sibpairs with SLE was based on mapping studies in murine lupus and may be an important step toward identifying a new disease-susceptibility gene in patients. Since the genes that predispose to autoimmunity are probably related to key events in pathogenesis, their identification in patients and murine models will almost certainly provide important insight into the breakdown of immunological self-tolerance and the cause of autoimmune disease.