B lymphocyte development progresses through several critical stages involving initial establishment of the antigen receptor repertoire and, thereafter, cellular selection influenced by the self-microenvironment. Strong self-reactivity leads to deletion or inactivation of these cells during development, a process termed “negative selection” or “tolerance.” However, cells with receptors specific for certain self-antigens are not treated in this way and persist for a long time without provoking autoimmune disease. Our research explores why such natural autoreactive lymphocytes should exist, the mechanisms whereby they develop, their functional significance, and their potential for dysregulation in relation to autoimmune/lymphoma disease development.