Stable graft function in the absence of maintenance immunosuppressive therapy (IS) is observed in some kidney recipients and in approximately 20% of liver recipients. Identification of these "operationally tolerant" recipients would constitute a major achievement in that it would allow for the widespread application of IS minimization strategies in the clinic. The use of gene expression profiling has provided promising results in the characterization of tolerant transplant recipients. We review here the available information on the use of transcriptional biomarkers to identify transplantation tolerance in the clinic and discuss some of the limitations of such strategy.