After many years of debate, there is now general agreement that B cells can participate in the immune response to cardiac transplants. Acute antibody-mediated rejection (AMR) is the best defined manifestation of B cell responses, but diagnostic and mechanistic questions still surround AMR. Many complement dependent mechanisms of antibody-mediated injury have been elucidated. C5 has become a therapeutic target that may not just truncate complement activation, but also may tip the balance away from inflammation by altering macrophage function. Additional complement independent effects have been identified. These may escape diagnosis and progress to chronic graft injury. The function of B cell infiltrates in cardiac transplants is even more enigmatic. Nodular endocardial infiltrates that contain B cells and plasma cells have been described in protocol biopsies of cardiac transplants for decades, but an understanding of their significance is still evolving based on more critical morphological and molecular evaluation of these infiltrates. A range of infiltrates containing B cells has also been described in the epicardial fat in transplants with advanced chronic rejection. B cells have been observed in endocardial and epicardial tertiary lymphoid nodules, but their impact on antigen presentation or antibody production remains to be determined. Experimental models in small and large animals suggest that B cells could be essential for the formation of lymphoid nodules through cytokine production. Similarly, the role of proinflammatory adipokines in the formation or function of epicardial lymphoid nodules has not been studied. These clinical observations provide critical questions to be addressed in experimental models.