T-regulatory cells (Tregs), a subset of CD4(+)CD25(+) lymphocytes, have the functional ability to suppress alloimmune responses in vitro and in vivo. Conditions that promote their development and enhance their biological function may be attractive for promoting unresponsiveness to organ transplants. Among the various mechanistic influences of sirolimus, one of its properties as an in vivo agent is to enhance Treg development and function. Therefore, sirolimus is being evaluated as a component of strategies to promote tolerance in organ transplant recipients. On the other hand, Treg promotion by sirolimus may be offset by other properties such as its influence on T-memory cells and B-cell activation. Other immunosuppressive agents will likely need to be used in combination with sirolimus to control the B-cell response. The development of novel genotypic markers of tolerance for liver and kidney transplant recipients should enhance our ability to measure the impact of immunosuppressive strategies with respect to their ability to promote tolerance in the clinical setting.