The formulation of therapeutic strategies to enhance immune-mediated tumor destruction is a central goal of cancer immunology. Substantive progress toward delineating the mechanisms involved in innate and adaptive tumor immunity has improved the prospects for crafting efficacious treatments. Schemes under active clinical evaluation include cancer vaccines, monoclonal antibodies, recombinant cytokines, and adoptive cellular infusions. While these manipulations increase tumor immunity in many patients, the majority still succumbs to progressive disease. Detailed analysis of subjects on experimental protocols together with informative studies of murine tumor models have begun to clarify the parameters that determine therapeutic activity and resistance. These investigations have highlighted efficient dendritic cell activation and inhibition of negative immune regulation as central pathways for intervention. This review discusses the development of genetically modified whole tumor cell vaccines and antibody-blockade of cytotoxic T lymphocyte associated antigen-4 (CTLA-4) as immunotherapies targeting these key control points. Early-stage clinical testing raises the possibility that combinatorial approaches that augment dendritic cell-mediated tumor antigen presentation and antagonize negative immune regulation may accomplish significant tumor destruction without the induction of serious autoimmune disease.