The development of biochemical and genetic schemes to characterize cancer antigens led to the recognition that malignant melanoma frequently evokes a host response. While the generation of brisk T-cell infiltrates in early stage disease is correlated with prolonged survival, host reactions in most cases are insufficient to impede tumor progression. One variable that may limit the potency of the host response against nascent melanoma is the mixture of cytokines present in the tumor microenvironment. In a murine melanoma model, we identified granulocyte–macrophage colony stimulating factor (GM-CSF) as the most potent molecule for augmenting tumor immunity following gene transfer into melanoma cells. Vaccination with irradiated melanoma cells engineered to secrete GM-CSF enhances host responses through improved tumor antigen presentation by recruited dendritic cells and macrophages. Melanoma-specific CD4+ and CD8+ T-cells, CD1d-restricted NKT-cells, and antibodies mediate tumor rejection. Initial testing of this immunization strategy in patients with metastatic melanoma revealed the consistent induction of cellular and humoral antitumor responses that provoked the extensive necrosis of distant metastases without significant toxicity.