Although in vivo priming of CD8⁺ cytotoxic T lymphocytes (CTLs) generally requires the participation of CD4⁺ T-helper lymphocytes,, the nature of the ‘help’ provided to CTLs is unknown. One widely held view is that help for CTLs is mediated by cytokines produced by T-helper cells activated in proximity to the CTL precursor at the surface of an antigen-presenting cell (APC). An alternative theory is that, rather than being directly supplied to the CTL by the helper cell, help is delivered through activation of the APC, which can then prime the CTL directly. CD40 and its ligand, CD40L, may activate the APC to allow CTL priming. CD40L is expressed on the surface of activated CD4⁺ T-helper cells and is involved in their activation and in the development of their effector functions,. Ligation of CD40 on the surface of APCs such as dendritic cells, macrophages and B cells greatly increases their antigen-presentation and co-stimulatory capacity^,,,. Here we report that signalling through CD40 can replace CD4⁺ T-helper cells in priming of helper-dependent CD8⁺ CTL responses. Blockade of CD40L inhibits CTL priming; this inhibition is overcome by signalling through CD40. CD40–CD40L interactions are therefore vital in the delivery of T-cell help for CTL priming.