Genetic factors play a major role in the development of lupus. More than 5% of cases are familial, and the concordance rate between identical twins is 40%. Genetic studies in mice suggest a complex mechanism of transmission involving interactions among several susceptibility genes and, probably, protective genes. Genetic studies in humans have identified nearly 50 chromosomal areas possibly involved in lupus transmission. Significant linkage has been found for at least six regions, two on chromosome 1, one near the HLA region on chromosome 6, and three on chromosomes 2, 4, and 16, respectively. Many candidate genes have been identified based on their location or possible pathogenic effects. Specific characteristics of the HLA region, as well as complement factor deficiencies, may promote nuclear antigen presentation, thereby triggering autoantibody production. The genetic polymorphism of cytokines and, perhaps, of the T-cell receptor (TCR) may contribute to deregulate lymphocyte activity. The polymorphism of the Fc receptors of immunoglobulins may affect immune complex clearance, thereby promoting tissue damage. Further genetic studies are needed to enrich the fund of knowledge on lupus and to identify new targets for treatment.