Despite advances in transplant immunosuppression, long-term renal allograft outcomes remain suboptimal because of the occurrence of rejection, recurrent disease, and interstitial fibrosis with tubular atrophy following kidney transplantation. This is largely due to limitations in our understanding of allogeneic processes coupled with inadequate post-kidney transplant surveillance strategies. The concept of donor-derived cell-free DNA as a signal of allograft stress has therefore been rapidly adopted as a noninvasive monitoring tool. Refining it for effective clinical use, however, remains an ongoing effort. Furthermore, its potential to unravel new insights in alloimmunity through novel molecular techniques is yet to be realized. This presentation summarizes current knowledge and active endeavors to optimize cell-free DNA-based diagnostic techniques for clinical use in kidney transplantation. In addition, the integration of DNA methylation and microRNA may unveil new epigenetic signatures of allograft health and is also discussed. Directing research initiatives toward these aspirations will not only improve diagnostic precision but may foster new paradigms in transplant immunobiology.