Summary: The crafting of genetic and biochemical techniques to identify cancer antigens yielded the unexpected discovery that immune recognition of tumors regularly accompanies cancer development. The failure of the host to suppress tumor formation or attenuate disease progression may thus reflect the limited immunogenicity of nascent tumors. One critical determinant of host immunity is the mixture of cytokines produced in the tumor microenvironment. We have compared a large number of secreted and surface molecules for their relative abilities to augment tumor immunity following gene transfer into cancer cells. In multiple murine models, granulocyte‐macrophage colony stimulating factor (GM‐CSF) proved to be the most potent immunostimulatory product. Vaccination with irradiated tumor cells engineered to secrete GM‐CSF involves enhanced tumor antigen presentation by recruited dendritic cells (DCs) and macrophages; the coordinated functions of CD4⁺ and CD8⁺ T cells, CD1d‐restricted NKT cells and antibodies mediate protective immunity. The evaluation of this vaccination strategy in patients with advanced melanoma revealed the consistent induction of cellular and humoral antitumor responses capable of effectuating substantial necrosis of distant metastases. The formulation of simplified methods for manufacturing autologous, GM‐CSF‐secreting tumor cells has enabled more extensive clinical testing in diverse patient settings.