Models of the differentiation of memory CD8+ T cells that replicate during secondary infections differ over whether such cells had acquired effector function during primary infections. We created a transgenic mouse line that permits mapping of the fate of granzyme B (gzmB)- expressing CD8(+) T cells and their progeny by indelibly marking them with enhanced yellow fluorescent protein ( EYFP). Virus- specific CD8(+) T cells express gzmB within the first 2 days of a primary response to infection with influenza, without impairment of continued primary clonal expansion. On secondary infection, virus- specific CD8(+) T cells that became EYFP+ during a primary infection clonally expand as well as all virus- specific CD8(+) T cells. Thus, CD8(+) T cells that have acquired an effector phenotype during primary infection may function as memory cells with replicative function.