Allograft rejection-like tolerance is a T-cell–mediated event. Acquisition of transplant tolerance, however, is a learned process, and T cells need to engage actively in alloantigens to learn to tolerate the graft. T-cell growth factors play an important role in regulating multiple aspects of the allograft response. It is true that T-cell growth factors can drive clonal expansion and functional maturation of alloreactive T cells; therefore, targeting growth factors and their receptor components remains one of the key aspects in transplantation. There is compelling evidence that growth factors also regulate the induction of peripheral allograft tolerance through programming activated T cells for apoptosis and guiding the development of regulatory T cells. Thus, understanding precisely the role of T-cell growth factors in regulating T-cell homeostasis and in developing active immune regulation is critically important in transplant tolerance.