The different threshold of activation for memory T cells compared to that of naïve T cells makes them resistant to immunomodulation, thus representing a barrier to tolerance. Recently it has been demonstrated that homeostatic proliferation and heterologous immunity represent two naturally occurring and distinct processes that can generate memory T cells. Homeostatic proliferation refers to the process by which, in a lymphodeficient host, normal T cells ‘spontaneously’ proliferate in response to self-MHC–peptide complexes. Heterologous immunity refers to a process in which a response to one or more infectious agents generates effector/memory T cells with cross-reactive specificities. Recent new studies have defined the importance of these processes in transplantation models and implicated strategies to induce transplantation tolerance.