Although considerable progress has occurred in kidney transplantation, allograft loss remains a substantial unresolved issue, leading to increased morbidity, mortality, and costs. Preserving, protecting, and extending the functional integrity of allografts is paramount to providing maximal benefits. To this end, identifying critical immunopathologic pathways and biomarkers associated with allograft attrition, with attendant development of rational therapeutic interventions, has emerged as one of the most important objectives of transplant medicine. B-cells and donor-specific anti-HLA antibodies (DSA) are now recognized as important mediators of allograft injury and loss. These findings have led to a renewed interest in therapies that modify B-cells and antibodies. Early experience with desensitization protocols coupled with improved diagnostics for DSAs and renal pathology have greatly improved transplant rates and outcomes for patients once considered at high risk for poor outcomes. Therapies aimed at B-cells and antibodies include high-dose intravenous immunoglobulin (IVIG), plasma exchange (PLEX) with low-dose IVIG, and IVIG combined with rituximab. Developing therapies include proteasome inhibitors aimed at plasma cells, newer monoclonal antibodies that block B-cell growth factors, and modifiers of complement-mediated injury. Here we discuss the importance of B-cells and DSAs as mediators of allograft injury and the evolution of therapies aimed at reducing their impact on allograft survival.