The impact of memory T cells on graft rejection and tolerance induction in transplant recipients is well recognized, particularly in clinical settings. This review discusses how alloreactive memory T cells are generated, either directly by alloantigen sensitization or indirectly by cross-reactive memory T cells against environmental antigens. Examples are provided of memory T-cell resistance to one of the most effective tolerance induction strategies today,ie, costimulation blockade, followed by a literature review on the role of memory T cells, especially of CD8 phenotype, in host immunity. The generation of distinct memory T-cell subsets, their different costimulation requirements for activation, and homeostasis are analyzed in the context of novel therapeutic strategies. Thus, modifications in current immunosuppressive regimens or adjunctive use of new agents is needed to control memory T-cell–mediated transplant rejection successfully. Indeed, comprehensive basic research on alloreactive memory T cells is warranted to develop much-needed specific strategies to overcome this seemingly formidable obstacle in the allograft rejection cascade.