The nucleosome is a large protein-nucleic acid complex involved in DNA packing and in controlling genetic information. Under circumstances described below, this component, normally sequestered in the cell nucleus, is released into the extracellular milieu and then is easily accessible to cells of the immune system. For still not completely understood reasons, nucleosomes become immunogenic under particular conditions. Thus, anti-nucleosome autoantibodies (autoAb) have been described in connective tissue diseases and especially in systemic lupus erythematosus (SLE). This review describes the mechanisms leading to nucleosome production and anti-nucleosome autoimmunity, as well as the pathogenesis associated with nucleosomes.