The immune management of organ transplant recipients is imperfect. Beyond general dosing guidelines for immunosuppressive agents and clinical diagnostic tests for rejection or infection, there are few objective tools to determine the aggregate status of a patient's alloimmune response or protective immune capacity. The lack of prognostic precision significantly contributes to patient morbidity and reduces long-term allograft survival after kidney transplantation. Noninvasive biomarkers that could serve as predictive tools or surrogate end points for rejection might help clinicians individualize immunosuppression and allow for early intervention, ideally prior to clinically evident organ dysfunction. Although the growing understanding of organ rejection has provided numerous candidate biomarkers, none has been confirmed in robust validation studies as sufficiently useful to guide clinical practice independent of traditional clinical methods. In this Review, the general characteristics of biomarkers and surrogate end points; current biomarkers under active clinical investigation; and the prominent barriers to the translation of biomarkers into clinical practice are discussed.