The goal of harnessing the immune system to effectively eradicate neoplastic disease will require the generation of robust Th-1 type immunity and durable immunological memory against the antigenic repertoire that differentiates normal self from neoplastic self. While the literature presents a very mixed picture as to the requirement of T-cell help for the generation of both primary and memory CTL responses, there appears to be a general consensus that CD4(+) T-cell help will be required to generate durable responses against self cancer antigens that are devoid of foreign PAMPs and for which high-affinity T-cell clones have been deleted as a consequence of thymic selection. Here we comment briefly upon the characterization of an emerging regulatory pathway that enhances Th-1 polarization and CD8(+) CTL responses by a mechanism dependent upon CD40L-mediated T-cell help. Further, we speculate that the full elucidation of this mechanism might be generally useful in answering some unresolved questions regarding the initiation of Th-1 polarized responses.