There is increasing evidence that in systemic lupus erythematosus, nucleosomes, the basic chromatin component, represent both a driving immunogen and a major in vivo target for antibodies. Either a disturbed apoptosis or a reduced clearance of apoptotic cells by phagocytes may lead to an increased exposure of apoptotic nucleosomes to the immune system. These nucleosomes, which have been cleaved and modified during the process of apoptosis, escape normal clearance and encompass epitopes that normally are not encountered by the immune system. This may then lead to tolerance breaking and autoimmunity by the activation of nucleosome-specific autoreactive T cells (that help B cells) and subsequently to the production of anti-nucleosome, anti-histone and anti-DNA autoantibodies. Some anti-nucleosome antibody subsets are pathogenic and are involved in the nephritogenic process in systemic lupus erythematosus. Accordingly, several studies reported: (i) increased plasma circulating nucleosomes that positively correlated with an active disease, (ii) nucleosomes in typical glomerular deposits as well as in the basement membrane of non-lesional skin of systemic lupus erythematosus patients and (iii) a close correlation between nephritis and the presence of anti-nucleosome antibodies. Recent studies reported anti-nucleosome antibodies also in primary anti-phospholipid syndrome and particularly in patients with associated lupus-like disease.