Whole tumor cells that secrete GM-CSF have been tested in clinical trials and have demonstrated early evidence of safety and clinical activity. The intradermal administration of these cells induces a massive infiltration of dendritic cells, which process and present tumor antigens to activate tumor-specific CD4+ and CD8+ T-cells. However, trial design flaws limit the phase III evaluation of this vaccine platform. Preclinical and clinical data suggest the development of GM-CSF-secreting tumor vaccines should be continued in combination with drugs that enhance vaccine activity by mitigating immune tolerance or augmenting costimulatory pathways of T-cell activation.