Memory T cells differ from naive T cells in that they respond more rapidly and in greater numbers. In addition, memory T cells are generally believed to be less susceptible to tolerance induction than naive T cells. In this study, we show that this is not the case. Using two different methods of tolerance induction, peptide-induced tolerance and crosstolerance, we present evidence that memory CD8(+) T cells are as susceptible to tolerance as naive cells. These results have a direct impact on manipulating T cell responses to self-antigens in order to improve immunotherapy of cancer and autoimmune diseases.