A comparative analysis of vaccination with irradiated, murine tumor cells engineered to express a large number of immunostimulatory molecules established the superior ability of granulocyte‐macrophage colony‐stimulating factor (GM‐CSF) to evoke potent, specific, and long‐lasting anti‐tumor immunity. Early stage clinical testing of this vaccination strategy in patients with diverse solid and hematologic malignancies revealed the consistent induction of a coordinated humoral and cellular reaction that effectuated substantial tumor destruction. Nonetheless, most subjects eventually succumbed to progressive disease, implying that additional immune defects remained to be addressed. More detailed investigations of the mechanisms underlying protective immunity in murine systems together with the characterization of the anti‐tumor reactions of patients who achieved durable clinical benefits in response to immunotherapy uncovered several pathways that restrain the efficacy of GM‐CSF‐secreting tumor cell vaccines. These include milk fat globule epidermal growth factor protein‐8 expansion of forkhead box protein 3⁺ regulatory T cells, cytotoxic T‐lymphocyte antigen‐4‐mediated negative costimulation, and soluble major histocompatibility complex class I chain‐related protein A suppression of NKG2D‐dependent innate and adaptive anti‐tumor cytotoxicity. Together, these results define key regulatory circuits that attenuate immune‐mediated tumor destruction and suggest novel combinatorial therapies that might enhance the clinical activity of GM‐CSF‐secreting tumor cell vaccines.