Purpose of review: Dramatic improvement in short-term results after kidney transplantation has fostered a change in focus for clinical research: further improvement in patient outcomes requires better understanding of late allograft failure. Recent findings: As recently as a decade ago, with clinicians and investigators besot by the mistaken assumption that 'rejection' was under control, most late allograft failure was attributed to calcineurin inhibitor nephrotoxicity. Application of newer laboratory-based techniques (C4d staining, solid-phase antibody assays, and molecular profiling) has resulted in a major shift in understanding late graft failure. New data from both clinic and laboratory indicate immunologic injury, perhaps potentiated by drug minimization, as the predominant cause of late allograft failure. Summary: This review traces our evolving understanding of the problem and what looks to be a paradigm change that offers new promise of effective intervention to improve long-term outcomes. © 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins.