The human immune system is comprised of several types of cells that have the potential to eradicate tumors without inflicting damage on normal tissue. Over the past decade, progress in the understanding of tumor biology and immunology has offered the exciting possibility of treating malignant disease with vaccines that exploit the capacity of T cells to effectively and selectively kill tumor cells. However, the immune system frequently fails to mount a successful defense against cancers despite vaccination with tumor-associated antigens. The ability of these vaccines to generate an abundant supply of armed effector T cells is often limited by immunoregulatory signaling pathways that suppress T cell activation. In addition, many tumors create a local microenvironment that inhibits the function of T cells. The attenuation of these pathways, which facilitate the evasion of tumors from immune surveillance, thus represents a potentially effective approach for cancer immunotherapy. Specifically, it may be of interest to modify the properties of dendritic cells, T cells, and tumor cells to downregulate the expression of proteins that diminish the immune response to cancers. RNA interference (RNAi) techniques have developed into a highly effective means of intracellular gene ‘knockdown’ and may be successfully employed in this way to improve cancer immunotherapies. This strategy has recently been explored both in vitro and in vivo, and has generated significantly enhanced antitumor immunity in numerous studies. Nevertheless, several practical concerns remain to be resolved before RNAi technology can be implemented safely and efficiently in humans. As novel developments and discoveries in molecular biology rapidly continue to unfold, it is likely that this technology may soon translate into a potent form of gene silencing in the clinic with profound applications to cancer immunotherapy.