During the last few decades our knowledge of transplantation has been remarkably expanded to the point where transplants are a standard treatment modality. However, despite the fact that certain tolerogenic protocols seemed to be very successful in small animal models, researchers anticipated the same outcomes in humans, which has mostly not been true yet. Immunological memory is known to be one of the reasons for such discrepancies. Donor-specific memory T cells are thought to be a crucial barrier in transplant success due to their unique properties. Recently, efforts to overcome this issue have been made, and several protocols showed the inhibition of memory T cell functions both in vitro and in vivo. In this review, we discuss the role of memory T cells in transplant rejection and the rising strategies to overcome this barrier.