To avoid toxic side effects caused by permanent immunosuppressive treatment, research in transplantation focuses on new treatment strategies inducing tolerance or allowing drug weaning. Implementing drug minimization into clinical routine can be only safely achieved when guided by biomarkers reflecting the individual immune reactivity. We review recently described biomarkers and assays allowing identification of patients suitable for drug weaning or at risk of rejection. However, the majority of described biomarkers and assays have not been validated in prospective clinical trials. Thus, collaborative efforts are needed to design and perform prospective multicenter trials to validate the identified biomarkers across different laboratories.