Humoral alloimmunity of organ transplant recipient to donor can lead to antibody-mediated rejection (ABMR), causing thousands of organ transplants to fail each year worldwide. However, the mechanisms of adaptive immune cell responses at the basis of humoral alloimmunity have not been entirely understood. In this review, we discuss how recent investigations have uncovered the key contributions of T follicular helper (T_FH) and B cells and their coordinated actions in driving donor-specific antibody generation and immune progression towards ABMR. We show how recognition of the role of T_FH–B cell interactions may allow the elaboration of improved clinical strategies for immune monitoring and the identification of novel therapeutic targets to tackle ABMR that will ultimately improve organ transplant survival.