Systemic lupus erythematosus (SLE) is a complex autoimmune disease in which multiple genes appear to play important roles in pathogenesis. Hereditary deficiencies, both complete and partial, of several components of the complement system clearly predispose to lupus. HLA class II alleles appear to mediate specific autoantibodies, many of which are pathogenic. Modern molecular techniques are now providing insight into the specific major histocompatibility complex class II polymorphisms that are associated with different autoantibodies in SLE. Other genetic systems also may be important.