Operational tolerance in kidney transplantation tolerance is rare phenomenon. It concerns recipients who keep a good function of their graft without immunosuppressors for more than one year. A critical need in the field of transplantation tolerance is the identification of biomarkers able to detect precociously tolerance phenotype in stable recipient in order to adapt treatment and progressively stop immunosuppressive therapy. But many limitations in these studies slow the application in clinics of such tolerance signature. In this addendum article we talk about these limitations and potential new directions to improve our approach in the quest of tolerance biomarkers.