Ischemia-reperfusion injury (IRI) is an unavoidable consequence of kidney transplantation and a major contributor to delayed graft function (DGF). DGF, traditionally defined as the need for dialysis within the first week post-transplant, is linked to inferior graft and patient outcomes, prolonged hospitalization, and higher health care costs. IRI begins with tissue hypoxia, which triggers an inflammatory response on reperfusion. The renal tubule plays a critical role in complement synthesis, with local activation driving inflammation and graft immunogenicity more than circulating liver-derived complement. The lectin pathway is a key initiator of complement activation in hypoxic renal tubules, primarily through collectin-11's interaction with glycan ligands on hypoxic cells, with further amplification through the alternative pathway. Despite promising preclinical results, systemic complement inhibitors have not significantly improved DGF in clinical studies, likely due to inefficient targeting of ischemic renal tubules. Machine perfusion offers a novel approach to delivering therapeutics directly to donor kidneys. Notably, hypothermic machine perfusion has improved DGF rates and early graft outcomes. Emerging targeted delivery systems using extracellular vesicles or nanoparticle-based carriers also promise to deliver therapeutics to the sites of injury. Organ-targeted complement inhibition through machine perfusion or other targeted delivery systems represent compelling strategies for IRI prevention. Finally, multigenic xenografts engineered to prevent complement activation have shown initial promise in overcoming the complement-mediated barriers that continue to challenge allotransplantation in humans.