The complement system is a key element of the innate immune system, and the production of complement components can be divided into central (hepatic) and peripheral compartments. Essential complement components such as C3 are produced in both of these compartments, but until recently the functional relevance of the peripheral synthesis of complement was unclear. Here, we review recent findings showing that local peripheral synthesis of complement in a transplanted organ is required for the immediate response of the donor organ to tissue stress and for priming alloreactive T cells that can mediate transplant rejection. We also discuss recent insights into the role of complement in antibody-mediated rejection, and we examine how new treatment strategies that take into account the separation of central and peripheral production of complement are expected to make a difference to transplant outcome.