Although transplantation tolerance cannot be yet reliably achieved in humans, there is evidence that active immunosuppression contributes to the maintenance of quiescence. However, the mechanism that underlies quiescence and the precise identity of regulatory cells are not completely understood. We have demonstrated that allograft recipients who remain rejection-free display allospecific T-suppressor cells (Ts). Ts express the CD8(+) CD28(-) phenotype, recognize major histocompatibility complex (MHC) class I antigens, and suppress the up-regulation of costimulatory molecules induced by CD40 ligation of donor antigen presenting cells. The presence of Ts is inversely correlated with T cell alloreactivity to donor MHC peptides, alloantibody production, and rejection. Monitoring of Ts has been successfully used in our studies for tailoring immunosuppression in kidney and liver allograft recipients.