A central question in immunology is the origin of Long-Lived T cell memory that confers protection against recurrent infection. The differentiation of nai:ve T cell receptor transgenic CD8(+) cells into effector cytotoxic T Lymphocytes (CTLs) and memory CD8(+) cells was studied. Memory CD8(+) cells that were generated after strong antigenic stimulation were the progeny of cytotoxic effecters and retained antigen-specific cytolytic activity 10 weeks after adoptive transfer to antigen-free recipient mice. Thus, potential vaccines based on CTL memory will require the differentiation of naiive cells into post-effector memory T cells.