Summary: The observation that the glycolipid α-galactosylceramide (α-GalCer) is a potent stimulator of natural killer T (NKT) cells has provided an important means for investigating NKT cell biology. α-GalCer is presented on CD1d to the invariant NKT receptor, leading to interleukin-12 (IL-12) production by dendritic cells (DCs) and to NK cell activation. We review our research on the tumor-protective properties of α-GalCer, particularly the major role played by DCs. We compared administration of α-GalCer on mature DCs with soluble glycolipid and found that DCs induced more prolonged interferon-γ (IFN-γ) production by NKT cells and better protection against B16 melanoma. Human α-GalCer-loaded DCs also expanded NKT cell numbers in cancer patients. α-GalCer-activated NKT cells were then found to induce DC maturation in vivo. The maturing DCs produced IL-12, upregulated co-stimulatory molecules, and induced adaptive immunity to captured cellular antigens, including prolonged, combined CD4+/CD8+ T-cell immunity to dying tumor cells. Surprisingly, co-stimulator-poor tumor cells, if directly loaded with α-GalCer (‘tumor/Gal’) and injected intravenously, also induced strong NKT- and NK-cell responses. The latter killed the tumor/Gal, which were subsequently cross presented by CD1d on DCs to elicit DC maturation and prolonged adaptive T-cell immunity, which lasted 6–12 months. These findings help explain tumor protection via α-GalCer and urge development of the DC-NKT axis to provide innate and adaptive immunity to human cancers.