Memory T cells specific for donor antigens present a unique challenge in transplantation. In addition to expressing rapid and robust immune responses to a transplanted organ, memory T cells may be resistant to the effects of currently used graft-prolonging therapies. The increasing recognition that alloreactive memory T cells participate in transplant rejection is driving new lines of research focusing on understanding the immunobiology of alloreactive memory T cells and on designing novel therapies to specifically target memory T cells. The purpose of this review is to summarize the effects of existing immunosuppressive drugs and costimulatory blockade on functions of alloreactive memory T cells that undermine allograft survival.