For several decades, allograft rejection was believed to be mediated almost exclusively by cellular immune responses, but it is now realized that humoral responses also play a major role. Although directed typically against donor human leukocyte antigen, it is becoming increasingly evident that the antibody response can also target autoantigens that are shared between donor and recipient and that this autoantibody may contribute to graft rejection. Many aspects of transplant-induced humoral autoimmunity remain poorly understood and key questions persist; not least what triggers the response and how autoantibody causes graft damage. Here, we collate results from recent clinical and experimental studies in transplantation and autoimmune diseases to propose answers to these questions.