Understanding the development of autoimmunity is a crucial step toward improving the management, not only of autoimmune diseases, but also of tumors and primary immunodeficiency syndromes. The rapid expansion of knowledge on autoimmunity is fueling the development of a novel approach known as targeted immunotherapy. The present review will concentrate on ten areas where major advances have been achieved: 1) early regulation of B-cell mediated autoimmunity; 2) thymic regulation of tolerance to tissue-restricted antigens via the transcription factor AIRE; 3) role for a population of regulatory T cells (CD4+ CD25+ Tregs) with unique effects; 4) major role for dendritic cells in the development of autoimmunity in conditions such as lupus; 5) role for T cells in autoimmune diseases; 6) role for T cells in rheumatoid arthritis, with new data from a murine model of spontaneous arthritis related to a ZAP-70 mutation; 7) role for the environment via innate immunity, in particular mediated by the toll-like receptors (TLR); identification of new autoantigens with the description of sense-antisense peptides (e.g., proteinase 3-complementary proteinase 3); the immunosenescence concept, which suggests that some autoimmune diseases may be related to premature aging of the immune system; 10) identification of new immunotherapy targets, including costimulation pathway molecules (CD28, CTLA4), original activation systems (BAFF/BLyS), and receptors such as TLRs. These exciting insights into the pathogenic mechanisms underlying immune dysfunction will play a key role in advancing the field of immunorheumatology.