In their current study in this issue of the JCI, Martínez-Llordella et al. (1) have defined new markers in the peripheral blood of liver transplant patients that correlate with a state of tolerance. This finding has significant implications for the clinic, where these signatures can serve as a screening tool for patient management. Liver transplant recipients on standard-of-care immunosuppression can be screened for these defined tolerance signatures based on expressed gene profiles and cell subsets, as measured by microarray, quantitative real-time PCR, and flow cytometry. If patients score positively for the “protolerance” signature, a program of immunosuppression withdrawal would be initiated, leading to a potential increase in the proportion of liver transplant recipients who can live free of immunosuppressive drugs, thereby improving long-term outcomes and quality of life.