Systemic lupus erythematosus is a prototypic autoimmune disease characterized by antinuclear antibodies (ANAs), including pathogenic specificities to DNA. As shown by recent research, ANA production is a genetically determined process in which self antigens drive B and T cells that have escaped the normal mechanisms of tolerance. Although antibodies can bind isolated protein or nucleic acid species, the in vivo driving antigens likely exist as complexes that have been released from apoptotic cells. The clinical measurement of ANAs, although valuable in assessing diagnosis and prognosis, must nevertheless be interpreted with caution because ANAs, despite their disease associations, can occur in healthy individuals.