The immune receptors of lymphocytes are able to sense the nature of bound ligands. Through coupled signaling pathways the generated signals are appropriately delivered to the intracellular machinery, allowing specific functional responses. A central issue in contemporary immunology is how the fate of B lymphocytes is determined at the successive developmental stages and how the B cell receptor distinguishes between signals that induce immune response or tolerance. Experiments with mice expressing transgenes or lacking signal transduction molecules that lead to abnormal lymphocyte development and/or response are providing important clues to the mechanisms that regulate signaling thresholds at different developmental stages. The studies are also revealing novel potential mechanisms of induction of autoimmunity, which may have a bearing on the understanding of human diseases.—Hasler, P., Zouali, M. B cell receptor signaling and autoimmunity. FASEB J. 15, 2085–2098 (2001)