Autoreactive B cells are one of the key immune cells that have been implicated in the pathogenesis of systemic lupus erythematosus (SLE). In addition to the production of harmful auto-antibodies (auto-Abs), B cells prime autoreactive T cells as antigen-presenting cells and secrete a wide range of pro-inflammatory cytokines that have both autocrine and paracrine effects. Agents that modulate B cells may therefore be of potential therapeutic value. Current strategies include targeting B-cell surface antigens, cytokines that promote B-cell growth and functions, and B- and T-cell interactions. In this article, we review the role of B cells in SLE in animal and human studies, and we examine previous reports that support B-cell modulation as a promising strategy for the treatment of this condition. In addition, we present an update on the clinical trials that have evaluated the therapeutic efficacy and safety of agents that antagonize CD20, CD22 and B-lymphocyte stimulator (BLyS) in human SLE. While the results of many of these studies remain inconclusive, belimumab, a human monoclonal antibody against BLyS, has shown promise and has recently been approved by the US Food and Drug Administration as an indicated therapy for patients with mild to moderate SLE. Undoubtedly, advances in B-cell immunology will continue to lead us to a better understanding of SLE pathogenesis and the development of novel specific therapies that target B cells.