Central to the events of T-cell activation and acute allograft rejection is the production of T-cell growth factors, a family of cytokines with potent mitotic activities (ie, interleukin-2, -4, -7, -9, and -15) that drive the proliferation, clonal expansion, and functional maturation of alloreactive T cells. Thus, targeting T-cell growth factors or their receptor components remains one of the key aspects of transplantation immunology. However, there is compelling evidence that T-cell growth factors also regulate the acquisition of peripheral allograft tolerance through modulating apoptotic cell death of activated T cells and guiding the development of immune regulatory cells. Thus, understanding the individual and collective role of T-cell growth factors in allograft response may prove to be critically important in designing effective therapeutic strategies to promote transplantation tolerance.