Transplantation tolerance is the ultimate goal of organ transplantation. Natural regulatory T cells (Treg) have been expected to reach clinical applications for tolerance induction because their initial description. More than ten yr later, Treg have started moving from experimental animal models into clinical applications. Although the molecular mechanism of contact-dependent inhibition remains to be unraveled, alterations of Treg numbers have been shown in several human diseases: Whereas several autoimmune diseases have been reported to be associated with decreased Treg numbers, Treg are frequently accumulated in solid tumors and hematologic malignancies. Monitoring of Treg numbers could be instrumental in identifying patients with risk of graft failure and might help minimizing immunosuppressive therapy in transplant recipients. Molecular mechanisms of Treg proliferation and Treg elimination such as CD95 ligand (CD95L)-mediated apoptosis are currently explored for their clinical usability as therapeutical targets. Immunosuppressive drugs might modulate the number of Tregs. Expansion of the Treg numbers in vivo or in vitro resembles a novel therapeutical strategy to reach partial or even operational tolerance after organ transplantation.