Human systemic lupus is a heterogeneous disorder characterized by multisystem inflammatory disease and the production of a variety of autoantibodies. For many years, in our ignorance, we had the freedom to imagine numerous abnormalities which might give rise to lupus: defects of the immune system, viruses, major histocompatibility driven predispositions, complement or complement receptor defects, biochemical abnormalities, impaired DNA repair, sex hormone imbalances, and many others. Now, the basis for lupus in lpr/lpr mice has been uncovered: a mutation in fas. The normal Fas cell surface molecule is important in programmed cell death, apoptosis. The lpr-associated defect in Fas interferes with normal apoptosis, allowing persistence of self-reactive lymphocytes. This finding is especially exciting to those of us who have stressed lupus-associated defects in tolerance. It also illustrates the apparent antigen-nonspecific nature of an etiologic abnormality leading to lupus. The multigenic NZB disorder is less well dissected. Recent work points to defects in an unusual bone marrow progenitor population. Patients with systemic lupus erythematosus may have different and multiple pathogenic factors, including those listed above. We recently have found that some patients with lupus have persistence of T cells with random mutations, consistent with prior abnormal activation and, perhaps, impaired apoptosis. Future therapies of patients must consider both the heterogeneity and the multifactorial pathogenesis of the syndrome we call ''lupus.'' (C) 1994 Academic Press, Inc.