Late failure of a kidney transplant continues to be a major problem after transplantation, in spite of more potent immunosuppressive strategies and the focus of clinical management shifting toward prolonging long-term graft survival. It is now recognized that graft failure occurs because of two major complications: death with a functioning graft and intrinsic allograft failure. Recent studies of late kidney graft loss have indicated a complexity of findings, including etiologies that are both immune and non-immune. These studies suggest that late graft failure is not an inevitable fact and that further investigation into the etiology of transplant graft failure may lead to a new understanding of the biology that will provide novel therapeutic strategies and biomarkers. In this review, we will focus on late allograft failure due to intrinsic injury to the transplant. The role of immune monitoring will be discussed in the context of monitoring for ongoing injury or for identifying late injury. A variety of methodologies have been used, including genomics, proteomics, and metabolomics, not only for monitoring allograft injury but also for identifying markers of graft failure that are more sensitive than serum creatinine. The available studies, as they relate to late or chronic graft injury, will also be reviewed.