Tumor–specific immunity relies on interactions with the antigen receptors as well as costimulatory molecules, such as those of the CD28/B7 pathway and relatives of the TNFR gene family. Cytotoxic T lymphocytes specific for cellular antigens are in general primed by professional antigen–presenting cells that indirectly present antigens derived from cells in the periphery. This cross–priming of CD8⁺T cells requires signals provided by CD4⁺T helper cells. Although this dependency on [help’ for efficient cytotoxic T lymphocyte priming has been well documented, it was only recently that more mechanistic insight into the nature of this event has been obtained. In the absence of the CD4⁺T cells, signalling through CD40 can replace `help' required for priming of these CD8⁺T cells. These observations indicate that T cell help for cytotoxic T lymphocytes is mediated by CD40–CD40Ligand (L) interactions, most likely through activation of professional antigen–presenting cells that cross–present cellular antigens to these T cells.