Alloantibody can be a major barrier to successful organ transplantation; however, therapy to control antibody production or to alter its impact on the allograft remains limited. The goal of this review is to examine the regulatory steps that are involved in the generation of alloreactive B cells, with a specific emphasis on how known mechanisms relate to clinical situations in transplant recipients. Thus, we will examine the process of activation of mature, naïve B cells and how this relates to de novo antibody production. The role of long-lived plasma cells in persistent antibody production and the factors regulating their longevity will be explored. The regulation of memory B cells and their possible roles in alloimmunity also will be assessed. Finally, we will review current therapeutic approaches aimed at controlling alloantibody and assess their efficacy. By examining the pathways to antibody production mechanistically, we hope to identify important gaps in our current knowledge and gain insight into possible new therapeutic approaches to overcoming antibody in transplant patients.