There is growing awareness that B cells and alloantibodies are important mediators of both acute and chronic allograft injury. Unfortunately, few therapies are clinically available to mitigate the function of B cells or the effects of established alloantibody. As a result, many sensitized people await transplantation without a suitable donor, and several rejection syndromes are emerging that appear to involve B cells either as antibody producers or as antigen-presenting cells. In recognition of this unmet need in transplantation, the American Society of Transplantation organized a Symposium on B cells in Organ Transplantation to foster interest in this topic amongst basic researchers attending the annual meeting of the American Association of Immunologists. This manuscript will give an overview of the presentations from this symposium including the current risks of allosensitization, adaptive accommodation, approaches toward B-cell tolerance for allo- and xenoantigens and clinical application of these concepts in ABO incompatible neonatal cardiac transplantation.