Natural killer T (NKT) lymphocytes mediate a rapid reaction to the glycolipid drug α-galactosylceramide (αGalCer), which triggers release of large amounts of cytokines into the serum within 12 h, starting with interleukin 4 (IL-4). When αGalCer is administered to mice on dendritic cells (DCs) instead, the response is more prolonged (>4 days) and marked by a large expansion in IFN-γ–producing NKT cells as well as greater resistance to metastases of the B16 melanoma. Nevertheless, DCs from mice given free αGalCer are able to induce strong IFN-γ–producing NKT responses when transferred to naïve mice, but not when transferred to αGalCer-treated recipients. In the latter, the NKT cells are anergized and can respond to glycolipid only in the presence of supplemental IL-2. Therefore, when αGalCer is selectively targeted to DCs, mice develop a stronger, more prolonged and effector type of NKT response, but this response can be blocked by the induction of anergy after presentation of αGalCer on other cells.