Nucleosomes play a central role in the antinuclear antibody response in lupus. Lupus anti-dsDNA and antihistone antibodies directed toward nucleosomes belong together with nucleosome-specific antibodies, to a broad antinucleosome antibody family. Besides anti-dsDNA, nucleosome-specific antibodies have a major role in the pathophysiology of systemic lupus erythematosus (SLE) and emphasize the role of nucleosome-antinucleosome immune complexes. Antinucleosome immunoglobulin G antibodies are a more sensitive marker of SLE than anti-dsDNA, and are almost exclusively found in lupus, scleroderma, and mixed connective tissue diseases. An understanding of the key role of the nucleosome will likely make possible new therapeutic interventions in SLE, such as a tolerance induction to the subnucleosomal particles.