Human kidney transplantation tolerance exists, but the definition of true tolerance as defined by Billingham and colleagues suffers several key elements that cannot be demonstrated in humans. Indeed, human tolerance in transplantation is defined by different functional and clinical parameters, this is why in clinical transplantation we preferentially talk about operational tolerance. These patients are very rare and defined in the literature as immunocompetent patients with stable graft function without any immunosuppressive treatments. These patients are characterized by a stable graft function in the absence of histologic information since the biopsy is often lacking. In kidney transplantation, this state of operational tolerance is observed in two situations. It is sometimes detected by chance in patients who stop their immunosuppressive treatments due to incompliance or because of secondary effects (cancer, opportunistic infections). The principal goal in kidney transplantation and one of the reasons why so many people are interested in cases of operational tolerance in humans, is to be able to identify patients who are developing spontaneous tolerance to their transplants while under classical immunosuppression. Consequently, there is an increasing need to develop an assay to identify and differentiate such patients with specific and noninvasive methods. In this review we will discuss the various studies that attempt to identify these new biomarkers of tolerance thanks to gene expression profiling using microarrays or quantitative PCR that have become a benchmark for research in novel and informative transplant monitoring assays.