Accurate diagnosis of acute rejection remains a formidable challenge in organ transplantation. The current gold standard diagnostic test for acute rejection is histological examination of the transplanted organ. However, biopsy procedures are invasive and complications occur. Furthermore, sampling errors may bias the histological diagnosis. Not uncommonly, empiric anti-rejection therapy has to be provided prior to the availability of a confirmatory histological report. Thus, there is an urgent need for specific and sensitive noninvasive biomarkers of acute rejection. Herein, we review noninvasive strategies for the diagnosis of acute rejection of solid organ transplants.