The development of antigen-specific cells of the immune system, the T and B lymphocytes, creates a dilemma. On the one hand, survival of the organism depends upon the generation of a nearly limitless repertoire of potential antigen-binding specificities so that cells able to respond to pathogens are present prior to contact. However, by devising genetic strategies to maximize receptor diversity, the generation of T and B cells with autoreactive receptors is inevitable. B cells have an even greater opportunity than T cells to become autoreactive, since they may randomly alter the amino acid sequence and hence the specificity of their receptors during an immune response. Observing the system, one might wonder not why autoimmune diseases occasionally develop, but rather why they are not more frequent or even unavoidable. In this review, we examine the generation of B cells and their repertoire of antigen receptors, describe mechanisms that have evolved to prevent self-reactive B cells from causing autoimmune diseases, and discuss scenarios that may lead to a breakdown of self tolerance.