SummaryVertebrates mount strong adaptive immune responses to transplanted organs (allografts), but the mechanisms by which the innate immune system initiates this response are not completely understood. In anti‐microbial immunity, non‐self molecules associated with pathogens but not present in the host induce the maturation of innate antigen‐presenting cells (APCs) by binding to germ‐line‐encoded receptors. Mature APCs then initiate the adaptive immune response by presenting microbial antigen and providing costimulatory signals to T cells. How allografts activate APCs, however, is less clear, because allografts are presumably sterile. A widely accepted view is that inflammatory or ‘danger’ molecules released by dying graft cells at the time of transplantation trigger APC maturation and the T‐cell response that follows. Alternatively, it has been proposed that the introduction of microbial products during the surgical procedure could also alert the innate immune system to the presence of the transplanted organ. Here, we review why these hypotheses fail to fully explain how the alloimmune response is initiated after transplantation and summarize evidence that recognition of allogeneic non‐self by monocytes is a key event in triggering alloimmunity and graft rejection.