Antibody-mediated, humoral rejection has been recognized as a common cause of transplant dysfunction and is responsible for 30-50 % of failed allografts. The production of antibody is dependent on instructions from memory CD4+ T helper cells that interact with antigen-specific B cells. Recently, a specialized T-cell subset has been identified-T follicular helper (Tfh) cells-which support activated B cells via interleukin (IL)-21 after binding to the IL-21 receptor expressed by these B cells. Therefore, neutralizing the IL-21 pathway will selectively inhibit the allogeneic IL-21-driven Tfh- and B-cell functions. However, little is known of the role of Tfh cells in alloreactivity. In this review, we debate the role of Tfh cells in B-cell-mediated allogeneic responses by discussing their mechanisms of actions. In addition, we speculate about the use of agents that intervene in Tfh-B-cell interaction and consequently prevent or treat antibody-mediated rejection in patients after transplantation.