Systemic lupus erythematosus (SLE) is a debilitating autoimmune disease that can involve multi-organs. B cells play a central role in the immunopathogenesis via antibody-dependent and antibody-independent ways. Excessive autoantibodies production, hyperresponsiveness and prolonged survival of autoreactive B cells are characteristics of SLE. In this article, mechanisms of self-tolerance loss of B cells and promising B cell-targeting therapies in lupus are reviewed and discussed. Systemic lupus erythematosus (SLE), the paradigm of autoimmune disease with the underlying mechanisms involving multiple immunological abnormalities, is a severely debilitating disease with multi-organ involvement and diverse autoantibodies spectrum [1]. Among the multiple elements in the pathogenesis, B cells play a central role in SLE through antibody dependent and independent manners [2]. Presence of pathogenic autoantibodies is not only the hallmark of SLE and the clue for diagnosis, but also associated with characteristic pathological injury and specific clinical manifestations [3][4][5]. In addition, the pathogenic role of B cells is also attributed to its antibody independent functions, including but not limited to antigen presentation, T cell crosstalk, dendritic cells (DCs) recruitment, pro-inflammatory cytokine secretion. Why and how auto-reactive B cells in lupus lose self-tolerance, escape from central and peripheral checkpoints, become over-activated and spontaneously produce autoantibodies, are always the focus of clinical and basic research. Therefore, it is important to summarize our current knowledge about the underlying mechanisms of self-tolerance breakdown and pathogenic functioning pathways of B cells in SLE. So we review here about B cell biology in SLE, including its differentiation and selection, functioning and signaling, surviving and apoptosis, and the resulting potential therapeutic targets both in mice and human lupus.