Genetic factors strongly influence the risk for systemic lupus erythematosus (SLE). Studies in both animal models and humans suggest that SLE is a complex trait with contributions from multiple genes. Recent genetic studies have shown that polymorphisms at several loci, including the major histocompatibility complex, complement proteins, immunoglobulin receptors, cytokines, and other as yet unmapped genes, are associated with SLE. Ethnic factors are also important because some of these genetic associations are only found in certain populations. Murine models of SLE have provided rational candidate loci to begin genome-wide studies in humans. Promising results are now emerging from such studies.