Since it was shown in the early 1950s that it is possible to induce transplantation tolerance in neonates, immune tolerance strategies have been actively pursued. It was found that T cells play a critical role in graft rejection, but can also be major players in mediating transplantation tolerance. Consequently, many experimental systems focused on T cells, often with a complete exclusion of B cells from in vivo animal models. It is now becoming clear that in addition to T cells, B cells can mediate graft rejection and transplantation tolerance. In this issue of the JCI, Khiew et al. investigated the contribution of alloreactive B cells to transplantation tolerance using a mouse cardiac transplantation model. The authors revealed a distinct tolerant B cell phenotype possessing the ability to suppress naive B cells. These data lead to a better understanding of B cell contributions to transplantation tolerance, and may inform the development of future immune tolerance protocols.