Immunological memory protects organisms from recurrent challenge by pathogens. The persistence of a heightened reactive state initiated by antigenic challenge is mediated by long-lived memory lymphocytes. The survival of memory T cells is thought to require stimulation through the T cell receptor (TCR), sometimes by persistent antigen. However, memory T cells can survive in the absence of antigen, in which case TCR stimulation provided by cell surface self-peptide/ major histocompatibility complex (MHC) molecules and cytokines are required to sustain memory T cells. Recent work using mouse models has provided insights into the origin of memory T cells. Understanding the mechanisms that underlie the differentiation and persistence of memory T cells may improve the effectiveness of vaccines through the induction of T cell memory.