The requisite molecular interactions for CD8 T cell memory were determined by comparison of monoclonal naive and memory CD8(+) T cells bearing the T cell receptor (TCR) for the HY antigen. Naive T cells required only the right major histocompatibility complex (MHC) class I-restricting molecule to survive; to expand, they also needed antigen. In contrast, for survival, memory cells did not require the restricting MHC allele, but needed only a nonspecific class I; for expansion the correct class I, but not antigen, was required. Thus, maintenance of CD8 T cell memory still required TCR-MHC class I interactions, but memory T cells may have a lower functional activation threshold that facilitates secondary responses.