A long-standing paradox in cellular immunology concerns the conditional requirement for CD4⁺ T-helper (T_H) cells in the priming of cytotoxic CD8⁺ T lymphocyte (CTL) responses in vivo. Whereas CTL responses against certain viruses can be primed in the absence of CD4⁺ T cells, others, such as those mediated through ‘cross-priming’ by host antigen-presenting cells, are dependent on T_H cells^,,,. A clearer understanding of the contribution of T_H cells to CTL development has been hampered by the fact that most T_H-independent responses have been demonstrated ex vivo as primary cytotoxic effectors, whereas T_H-dependent responses generally require secondary in vitro re-stimulation for their detection. Here, we have monitored the primary and secondary responses of T_H-dependent and T_H-independent CTLs and find in both cases that CD4⁺ T cells are dispensable for primary expansion of CD8⁺ T cells and their differentiation into cytotoxic effectors. However, secondary CTL expansion (that is, a secondary response upon re-encounter with antigen) is wholly dependent on the presence of T_H cells during, but not after, priming. Our results demonstrate that T-cell help is ‘programmed’ into CD8⁺ T cells during priming, conferring on these cells a hallmark of immune response memory: the capacity for functional expansion on re-encounter with antigen.