Complement is an important component of the innate immune system whose function is integrated with the adaptive immune response. Since complement proteins are produced in virtually any cell in the body, it is important to question which pools of complement are responsible for what actions. This is particularly so in the case of complement-mediated renal disease, where distinct sites may require individualized approaches for therapy. From experimental and clinical evidence to date, it seems that the circulating pool of complement underlies much of the pathology traditionally associated with glomerular disease, including capillary wall injury. In contrast, the renal tubulointerstitium is the domain of local synthesis of complement, notably the axial component C3, principally expressed by the tubular epithelium. This means that therapeutic targeting will have to ensure penetration of the interstitial space in certain disorders. Likewise, monitoring of disease activity may benefit from evaluating this extravascular pool. Therapeutic and diagnostic applications in human disease are already taking this into account, with transplantation leading the way.